The TTR NM_000371.4:c.238A>G (NP_000362.1:p.(Thr80Ala)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Recombinant A60 TTR showed 86.2% thyroxine binding and 100% aggregation at pH 4.8, but clinical carrier testing found no significant binding change. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.TTR encodes transthyretin, a protein that transports thyroid hormones in the blood and cerebrospinal fluid and helps carry vitamin A. Abnormal transthyretin can form amyloid deposits, causing inherited conditions that may affect the peripheral nerves, heart, eyes, brain coverings, or other tissues. TTR is not known to have a direct cancer association.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met: the exact TTR p.Thr80Ala change is established as pathogenic in ClinVar and reported independently as the mature-protein T60A/A60 variant.
Met at supporting strength: recombinant A60 TTR showed 86.2% thyroxine binding and 100% aggregation at pH 4.8, but clinical carrier testing found no significant binding change.
Met at supporting strength: gnomAD v4.1 AF is 1.6728e-05, below the PM2 threshold of 0.0001, with 0 homozygotes.
Met at supporting strength: the variant is reported in an affected patient and affected brother within a familial amyloidosis kindred, supporting cosegregation in multiple affected relatives.
Met: REVEL 0.675 exceeds the generic PP3 supporting threshold of >=0.644 for missense variants.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS1 strong plus PS3, PM2, PP1, and PP3 supporting satisfy the generic ACMG/AMP combination of one Strong and four Supporting criteria.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 27 / 1,614,060 alleles. Recorded AF 1.6728e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.97706e-06; MAF= 0.00040%, 1/251442 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79214e-06; MAF= 0.00088%, 1/113738 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.675. Refer to the recorded PP3/BP4 rationale for interpretation.
14 Pathogenic · 1 Likely pathogenic · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 8 not met · 10 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS1 is met because the exact p.Thr80Ala protein change is established as pathogenic; the mature-protein notation T60A/A60 refers to the same substitution after accounting for the 20-residue signal peptide.
PM1, PM5, and PP2 remain not assessed because the supplied evidence lacks the required authoritative domain/hotspot, alternate same-residue pathogenic comparator, and gene-level benign-missense constraint evidence, respectively.
BP1 is not met because the supplied TTR evidence supports a missense amyloidogenic mechanism rather than primarily truncating disease causation.
Segregation evidence supports PP1 at supporting strength based on reports of the relevant TTR alanine-for-threonine variant in multiple affected relatives; no case-specific de novo or affected-relative non-segregation evidence is documented for PS2, PM6, or BS4.
Variant-specific biochemical evidence supports altered TTR behavior relevant to amyloid disease, but mixed assay results and lack of clinical diagnostic validation limit PS3 to supporting strength.
No well-established evidence demonstrates absence of damaging effect, so BS3 is not met.
No VCEP covers TTR in this case; generic ACMG/AMP 2015 rules govern.
PS4 is not met because affected-case observations are not accompanied by a matched control comparison sufficient to calculate or demonstrate OR/RR >5.0 with a confidence interval excluding 1.0.
PP4 and BP5 are not assessed because the case-level phenotype/family history and alternate molecular diagnosis information are absent.
PP5 and BP6 are not applied because the exact-variant ClinVar audit shows zero expert-panel submissions, and ordinary submissions or independently available publications do not satisfy the requested triggers.
PM3 is not applicable because the relevant TTR disorder is autosomal dominant rather than recessive.
BP2 is not assessed because the case lacks a second pathogenic variant and phase information establishing cis or trans configuration.
This is a missense variant; PP3/BP4 were adjudicated exclusively with REVEL under the generic missense path.
PP3 is met at supporting strength because REVEL 0.675 is >= 0.644; BP4 is not met because REVEL 0.675 is not <= 0.29.
No criteria match.
The variant is NP_000362.1:p.(Thr80Ala), also reported using mature TTR numbering as p.Thr60Ala/A60. ClinVar variation 13421 identifies NM_000371.4:c.238A>G (p.Thr80Ala) as Pathogenic with multiple submitters and no conflicts. Independent extracted reports describe the same TTR A60/T60A substitution in affected hereditary amyloidosis cohorts and recombinant-protein assays; the 20-residue signal-peptide numbering difference reconciles T60A/A60 with precursor-protein p.Thr80Ala. SpliceAI max delta is 0.00, so there is no supplied indication that this is being adjudicated as a splice-impacting change rather than the same protein change.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PS3 is met at supporting strength. Two variant-specific biochemical studies evaluated the mature TTR A60 substitution, equivalent to NP_000362.1:p.(T80A). Schwarzman et al. used recombinant human TTR, wild-type comparison, and three independent experiments; A60 showed reduced thyroxine binding (86.2 ± 5.45% of wild type), amyloid-beta aggregation inhibition of 26.7 ± 3.38% relative to no-TTR control, and complete TTR aggregation at pH 4.8, supporting altered protein behavior relevant to amyloid disease. Hammarström et al. studied five Appalachian carriers with DNA-confirmed variant status and a thyroxine-binding assay, but found no significant change in binding affinity, so the evidence is mixed and does not justify moderate or strong PS3 calibration. The studies are biologically relevant and include controls, but they were not demonstrated to be clinically validated, reproducible diagnostic-laboratory assays and the positive findings are model-dependent.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM2 is met at supporting strength. The generic SVI threshold supplied for this case is <=0.0001. The variant is present at very low frequency in gnomAD v4.1 (AF=1.6728e-05; 27/1614060 alleles; 0 homozygotes), with grpmax FAF=1.107e-05, and in gnomAD v2.1 non-cancer exomes at AF=4.22112e-06 (1/236904 alleles; 0 homozygotes). These values are below 0.0001, although the variant is not literally absent from controls.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The available family reports concern the exact TTR alanine-for-threonine variant corresponding to p.Thr80Ala under precursor-protein numbering. The literature describes familial amyloidotic polyneuropathy in a large kindred, including an affected patient and affected brother, and another report describes affected members with asymptomatic gene-carrying offspring. This supports cosegregation of the variant with the dominantly inherited phenotype in multiple affected relatives. The evidence does not provide a complete pedigree, a quantified meiosis count, or sufficiently detailed segregation data to justify a stronger level.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The variant is a missense substitution, NM_000371.4:c.238A>G (NP_000362.1:p.(Thr80Ala)); therefore the applicable generic PP3/BP4 path is REVEL only. REVEL is 0.675, meeting the published generic PP3 supporting threshold of >= 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI and BayesDel were not used for PP3 because SpliceAI is the path for intronic, synonymous, or splice-region variants, and no generic BayesDel strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only.
Generic ACMG/AMP PS4 requires a significant increase in affected individuals compared with controls, with OR/RR >5.0 and a confidence interval excluding 1.0. The verified literature extracts document the exact TTR p.(Thr80Ala)/mature T60A variant in affected hereditary amyloidosis cohorts or families, including 11.5% of non-V30M genotypes in a 130-patient ATTR-FAP trial (PMID:24368466), but they do not provide a matched unaffected-control comparison for this exact variant. gnomAD v4.1 reports 27/1,614,060 alleles (AF 1.6728e-05) in the general population, but no affected-case frequency from the same ascertainment frame is available, so an OR and 95% CI cannot be computed. The PS4-indexed literature_pass leads (PMIDs 1626556, 20301532, 2840822, 35802134, and 4079954) were not present as fetched full-text or paper-extract records; the available literature_pass ai_classified_papers contained no paper classified as PS4. Therefore, case observations and population frequency do not establish the required case-control enrichment.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
Generic ACMG/AMP PP5 requires a reputable source to recently report the variant as pathogenic when the evidence is not available to the laboratory for independent evaluation. The exact variant is reported as pathogenic in ordinary ClinVar laboratory/literature submissions, but ClinVar records no expert-panel submission (0 expert-panel submissions), and the relevant publications and extracts are available for independent review. The verified literature supports that TTR T60A/T80A is associated with hereditary amyloidosis, including the affected-patient and affected-brother observations in PMID:3722385, but that is independently inspectable evidence rather than an otherwise unavailable reputable-source assertion. Under the requested rule, PP5 is not applied.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The governing generic threshold is >=0.05, and the appropriate gnomAD filtering frequency is the grpmax FAF rather than the popmax point estimate. gnomAD v4.1 reports grpmax FAF=1.107e-05, far below 0.05; the highest observed subgroup point estimate, 0.000112022 (7/62488 alleles), is not used for BA1. The variant is also reported as pathogenic in ClinVar, so there is no basis to override the frequency result with a stand-alone benign call.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met on the available population evidence. The generic default is >=0.01, while gnomAD v4.1 grpmax FAF=1.107e-05, well below 0.01; the non-cancer datasets are also below this threshold (v2.1 non-cancer exomes AF=4.22112e-06; v3.1 non-cancer genomes grpmax FAF=4.88e-06). TTR familial amyloid polyneuropathy is described as autosomal dominant and late-onset, so the default 1% threshold is not independently sufficient to establish BS1 without a maximum-credible-frequency calculation, but the observed filtering frequencies are already orders of magnitude below it.
Allele frequency is greater than expected for the disorder.
BS3 is not met. The available variant-specific studies do not establish that TTR p.(T80A) has no damaging effect on protein function or splicing. One study found no significant change in thyroxine-binding affinity, but another controlled recombinant assay found reduced thyroxine binding and complete aggregation at pH 4.8, and the clinical study did not evaluate the full amyloidogenic function of TTR. Therefore, the negative thyroxine-binding result cannot support a well-established benign functional conclusion.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP1 is not supported for TTR. The supplied TTR literature describes hereditary amyloidosis as involving numerous disease-associated missense substitutions and reports missense genotypes such as T60A/A60 in affected cohorts and functional assays. It does not show that TTR disease is caused primarily by truncating variants; the available mechanism evidence instead centers on altered TTR protein stability, secretion, aggregation, and amyloid deposition.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense substitution, so BP4 must be judged on the REVEL path only. REVEL is 0.675, which is above the generic BP4 supporting cutoff of <= 0.29 and therefore does not support a benign/no-impact computational conclusion. The SpliceAI max delta of 0.00 is not used because splice prediction is not the applicable path for a missense variant; BayesDel is not available for generic ACMG strength assignment.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only.
Generic ACMG/AMP BP6 requires a reputable source to recently report the variant as benign when the evidence is not available to the laboratory for independent evaluation. The exact-variant ClinVar audit shows no expert-panel submissions and no benign or likely-benign expert-panel classification; the available literature instead reports TTR T60A/T80A in hereditary amyloidosis and is independently inspectable. Ordinary submissions, aggregate labels, and non-expert assertions cannot trigger BP6 under the requested rule, so BP6 is not applied.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-specific proband-parent trio data are documented. In particular, there is no documented confirmation of both maternity and paternity, no parental genotypes demonstrating absence of the variant, and no explicit statement that the proband had no family history. The available literature describes familial TTR amyloidosis, not a confirmed de novo occurrence in this case.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The supplied evidence shows no statistically significant hotspot and no COSMIC report, but generic PM1 requires a mutational hotspot or a critical, well-established functional domain without benign variation. No authoritative TTR domain annotation, hotspot definition, or gene-level benign-variation assessment is supplied, so PM1 cannot be adjudicated reliably.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The variant is a missense change at precursor-protein residue 80 (mature TTR residue 60), but the supplied candidate file contains no same-residue comparator variants and explicitly reports that classic PM5 candidate harvesting was not completed. The available extracted papers document the same T60A/A60 variant, not a different missense substitution at that residue, so a pathogenic alternate missense comparator cannot be confirmed.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No case-specific evidence establishes that NM_000371.4:c.238A>G arose de novo. The available records do not document an affected proband with both parents tested negative, nor do they document an assumed de novo event with the required parental-testing context. Familial reports of TTR p.Thr80Ala do not establish PM6 for this case.
Assumed de novo, but without confirmation of paternity and maternity.
The extracted literature supports that disease-associated TTR variation commonly involves missense substitutions and amyloidogenic protein behavior, but the supplied case evidence does not establish the required low rate of benign missense variation for TTR under a defined gene-level metric or threshold. Because both parts of PP2 must be supported, the criterion is not assessed.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The generic PP4 rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The supplied case evidence identifies the variant and its literature associations but does not provide the present patient's phenotype, family history, diagnostic findings, or a documented phenotype-specific differential. The criterion therefore cannot be assessed without case-level clinical information.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD shows no homozygotes (v2.1, v2.1 non-cancer, v3.1 non-cancer, and v4.1), but the available population records do not establish that any heterozygous carrier was a healthy adult at an age sufficient to exclude a late-onset TTR phenotype. The governing BS2 definition requires observation in a healthy adult and full penetrance expected at an early age; the relevant TTR disease is described as autosomal dominant late-onset, so unphenotyped gnomAD carriers cannot satisfy BS2.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
The available evidence does not document affected relatives who lack the variant. Reports of asymptomatic carriers are not, by themselves, lack of segregation in affected family members, particularly for this late-onset disorder. Therefore the BS4 requirement is not established, and the phenocopy caveat cannot be meaningfully evaluated from the available family data.
Lack of segregation in affected members of a family.
BP2 requires observation of this variant in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or in cis with a pathogenic variant in any inheritance pattern. The case evidence contains no second pathogenic variant and no parental, offspring, or other phase information establishing either trans or cis configuration. The TTR disorder is described as autosomal dominant, but inheritance mode alone cannot establish BP2 without the required allelic observation and phase.
BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The generic BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. The supplied evidence documents hereditary TTR amyloidosis observations but does not identify a particular case with a confirmed alternate pathogenic molecular cause of the disease. Absence of that case-level information prevents assessment rather than permitting BP5 to be applied.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000371.4:c.238A>G in TTR is a missense substitution predicted to produce NP_000362.1:p.(Thr80Ala). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for TTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is restricted to recessive disorders and requires the tested variant to be detected in trans with a pathogenic variant. The available case evidence identifies TTR hereditary amyloidosis as an autosomal dominant disorder, so the recessive-disorder applicability condition for PM3 is not met; no PM3 evidence is assessed.
PM3: For recessive disorders, detected in trans with a pathogenic variant
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000371.4:c.238A>G in TTR is a missense substitution predicted to produce NP_000362.1:p.(Thr80Ala). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for TTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000371.4:c.238A>G in TTR is a missense substitution predicted to produce NP_000362.1:p.(Thr80Ala). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for TTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000371.4:c.238A>G in TTR is a missense substitution predicted to produce NP_000362.1:p.(Thr80Ala). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for TTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in TTR, mapped onto the exon structure of NM_000371.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Remaining individuals7 / 62,488 | 0.00011 |
| European (non-Finnish)20 / 1,180,032 | 1.7e-05 |
| European (non-Finnish)1 / 113,738 | 8.8e-06 |
This variant is present in gnomAD v4.1 (AF= 1.6728e-05; MAF= 0.00167%, 27/1614060 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000112022; MAF= 0.01120%, 7/62488 alleles, homozygotes = 0); grpmax FAF= 1.107e-05.
This variant is present in gnomAD v2.1 (AF= 3.97706e-06; MAF= 0.00040%, 1/251442 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79214e-06; MAF= 0.00088%, 1/113738 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_000371.4:c.238A>G (NP_000362.1:p.(Thr80Ala)); therefore the applicable generic PP3/BP4 path is REVEL only. REVEL is 0.675, meeting the published generic PP3 supporting threshold of >= 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI and BayesDel were not used for PP3 because SpliceAI is the path for intronic, synonymous, or splice-region variants, and no generic BayesDel strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only.
The variant is a missense substitution, so BP4 must be judged on the REVEL path only. REVEL is 0.675, which is above the generic BP4 supporting cutoff of <= 0.29 and therefore does not support a benign/no-impact computational conclusion. The SpliceAI max delta of 0.00 is not used because splice prediction is not the applicable path for a missense variant; BayesDel is not available for generic ACMG strength assignment.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000371.4:c.238A>G in TTR is a missense substitution predicted to produce NP_000362.1:p.(Thr80Ala). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for TTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.675. BayesDel score = 0.355953.
10 paper records listed. 5 cited in the classification.
A60 FAC 86.2 + 5.45 26.7 + 3.38 100 ND ND
Location Table 1, Characterization of recombinant TTR variants
Context Recombinant human TTR variants expressed in E. coli, purified, and assessed for thyroxine binding, amyloid-beta aggregation inhibition, and TTR aggregation at pH 4.8, 6.2, and 6.8; results were means of three experiments +/- SD.
A previously reported family with amyloid polyneuropathy (FAP) was reinvestigated to determine the type of mutation in the transthyretin (prealbumin) molecule. Transthyretin was isolated from amyloid-laden myocardium and serum, and tryptic peptides were resolved by high-performance liquid chromatography. Amino acid sequencing of an anomalous peptide revealed an alanine-for-threonine substitution corresponding to position No. 60 of the transthyretin monomer.
Location PubMed abstract; family and variant description
Context Familial amyloid polyneuropathy kindred; biochemical characterization of transthyretin from amyloid and serum, with carrier detection by hybrid isoelectric focusing.
Non-V30M ATTR included T60A (11.5%), L58H (11.5%), F64L (3.1%), S50R (3.1%), and 17 other genotypes (eTable 2).
Location Results, Patient Characteristics, paragraph 2
Context International randomized, double-blind, placebo-controlled diflunisal trial in 130 patients with ATTR-FAP recruited from eight amyloid centers in five countries; T60A was reported among non-V30M genotypes.
a recently discovered kindred from the Appalachian area of the United States has an alanine substitution for threonine at position 60 of TBPA (16).
Location Introduction/Comments, page 1433; Results, page 1434; Table 1
Context Five individuals from an Appalachian familial amyloid polyneuropathy kindred; carrier status established by DNA restriction-fragment analysis and thyroxine-binding measured in vitro.
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant late-onset disorder characterized by the extracellular deposition of amyloid fibrils. Biochemical studies were conducted on amyloid from one patient and plasma prealbumin from his affected brother, both part of a large kindred from the Appalachian region of the United States.
Location PubMed abstract; study subjects and kindred description
Context Affected members of a large Appalachian familial amyloidotic polyneuropathy kindred; biochemical and molecular characterization of amyloid and plasma transthyretin.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 1.6728e-05; MAF= 0.00167%, 27/1614060 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000112022; MAF= 0.01120%, 7/62488 alleles, homozygotes = 0); grpmax FAF= 1.107e-05.
This variant is present in gnomAD v2.1 (AF= 3.97706e-06; MAF= 0.00040%, 1/251442 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79214e-06; MAF= 0.00088%, 1/113738 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (14 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory). (ClinVarID = 13421)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.675. BayesDel score = 0.355953.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.