The TTR NM_000371.4:c.148G>A (NP_000362.1:p.(Val50Met)) missense variant has not previously been reported in somatic cancers (COSMIC). 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 Val50Met change is reported in affected siblings with familial amyloidotic polyneuropathy and confirmed by RFLP and mass spectrometry.
Met at supporting strength: gnomAD v4.1 grpmax FAF is 0.00004182, below the 0.0001 PM2 supporting threshold.
Met at supporting: the ClinVar evidence trail reports segregation in >100 affected individuals from >95 families, but lacks family-level meiosis data for stronger evidence.
Met at supporting strength: REVEL 0.711 meets the PP3 threshold of >=0.644 but is below the moderate threshold of >=0.773.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS1 strong plus PM2, PP1, and PP3 supporting satisfy the generic ACMG/AMP combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 92 / 1,614,098 alleles. Recorded AF 5.69978e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000103395; MAF= 0.01034%, 26/251462 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000488599; MAF= 0.04886%, 3/6140 alleles, homozygotes = 0); grpmax FAF= 0.00010857.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.711. Refer to the recorded PP3/BP4 rationale for interpretation.
36 Pathogenic · 2 pathogenic · 1 Likely 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: 4 met · 6 not met · 13 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PP1 is met at supporting strength from the reported segregation in more than 100 affected individuals across more than 95 families.
PS2 and PM6 are not assessed because no proband-specific de novo or parental-testing evidence is documented.
BS4 is not assessed because no affected non-carrier or informative non-segregation observation is documented.
No VCEP covers TTR in this case, so the supplied generic ACMG/AMP rules govern.
PS4 was not assessed because the reviewed literature and population data do not provide exact-variant affected-versus-control counts sufficient to calculate the required OR and 95% CI.
PP5 and BP6 were restricted to exact-variant ClinVar expert-panel classifications as required; ClinVar reports no expert-panel submission for this variant.
The variant is missense (NP_000362.1:p.(Val50Met)); generic PP3/BP4 therefore use REVEL only.
REVEL 0.711 meets PP3 supporting but does not meet PP3 moderate or strong, and it does not meet BP4 at any strength.
No criteria match.
The observed variant is NP_000362.1:p.(Val50Met), corresponding to mature-protein TTR V30M. PMID:11409034 reports the same amino-acid substitution as TTR V30M in two affected siblings with familial amyloidotic polyneuropathy and confirms the variant molecularly by RFLP and mass spectrometry. This is the same amino-acid change, not merely a change at the same residue, and the report establishes its disease-associated occurrence; the paper's mature-protein numbering is reconciled to the case's precursor numbering by the 20-residue signal-peptide offset.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PM2 is met at supporting strength. Under the generic default, the applicable all-comers gnomAD v4.1 filtering grpmax FAF is 0.00004182 (0.004182%), which is at or below the supplied PM2 supporting threshold of 0.0001 (0.01%). The variant is not absent, but it is present at an extremely low frequency in a large population dataset (92/1,614,098 alleles; no homozygotes), supporting PM2 rather than a stronger absence claim. The v4.1 point estimate for Remaining individuals is not used in place of the filtering FAF.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
ClinVar's evidence trail for the exact variant includes a clinical submission stating that NM_000371.4:c.148G>A segregated with disease in more than 100 affected individuals from more than 95 families. This directly supports co-segregation in multiple affected family members for a TTR-related disease, so generic PP1 is met at supporting strength. The available record does not provide family-level meiosis counts or an auditable pedigree-by-pedigree dataset to justify a stronger assignment under the supplied rule.
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, so the applicable computational path is REVEL only. REVEL is 0.711, meeting the generic PP3 supporting threshold of >= 0.644 but not the moderate threshold of >= 0.773 or the strong threshold of >= 0.932. Therefore PP3 is met at supporting strength.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The governing PP5 rule concerns a reputable source reporting the variant as pathogenic when the evidence is unavailable for independent evaluation. Under the specified generic PP5 rule, application is restricted to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification. ClinVar variation 13417 has no expert-panel submission; its Pathogenic and Likely pathogenic assertions are from ordinary submitters and laboratory submissions. The exact-variant literature reports are not an expert-panel ClinVar classification and therefore do not satisfy this criterion under the required rule.
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 applicable default all-comers gnomAD v4.1 data show grpmax FAF=0.00004182 (0.004182%), far below the generic stand-alone threshold of 0.05 (5%). The highest population point estimate, 0.000223986 in Remaining individuals, is not used for this decision because the rule requires the filtering grpmax FAF and the population-frequency evidence does not approach the BA1 threshold. ClinVar reports a pathogenic consensus for this well-established TTR Val50Met allele, which is also inconsistent with ending classification using a default BA1 call; in any event, the required FAF threshold is not reached.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met on the available frequency evidence. The default all-comers gnomAD v4.1 filtering grpmax FAF is 0.00004182 (0.004182%), below the generic BS1 default threshold of 0.01 (1%). Although TTR Val50Met is a reduced-penetrance/late-onset disease allele context in which the 1% default should not be applied mechanically, no maximum-credible-frequency calculation is needed here because the observed filtering FAF is already far below 1%; the elevated Remaining-individuals popmax point estimate of 0.000223986 is not the permitted frequency figure for BS1.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BP1 is not supported because the supplied TTR disease evidence identifies missense variation as the disease-associated mechanism: TTR V30M/precursor Val50Met is reported in familial amyloidotic polyneuropathy, and the case evidence describes the variant as missense. Nothing in the supplied evidence establishes that TTR disease is caused primarily by truncating variants; therefore the gene-level premise of BP1 is not met.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense substitution, so the applicable computational path is REVEL only. REVEL is 0.711, which exceeds the generic BP4 supporting cutoff of <= 0.29 and is therefore not evidence for a tolerated effect. The SpliceAI score and BayesDel score are not used for BP4 in this missense situation.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The governing BP6 rule concerns a reputable source reporting the variant as benign when the evidence is unavailable for independent evaluation. Under the specified generic BP6 rule, application is restricted to an exact-variant ClinVar expert-panel Benign or Likely benign classification. ClinVar variation 13417 has no expert-panel submission and contains Pathogenic/Likely pathogenic rather than expert-panel Benign/Likely benign assertions. BP6 is therefore not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The available evidence does not document a de novo occurrence in a proband with both maternity and paternity confirmed, nor does it establish absence of a family history for this patient. Therefore, the PS2 requirement cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The case evidence identifies PMID:6736244 as a functional study of the exact TTR Val30Met variant, reporting structural and biochemical characterization of transthyretin and altered amyloid-fibril properties. This is directionally supportive of a damaging effect, but the available evidence does not document a reproducible, validated clinical-laboratory assay with appropriate controls, and no generic ClinGen SVI strength-calibration threshold for PS3 is supplied in the governing rules. Therefore PS3 cannot be assigned a defensible strength from the permitted rules and is not assessed.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
The governing ACMG/AMP PS4 rule requires a significantly increased prevalence in affected individuals compared with controls; the supplied rule's Note 1 specifies RR or OR >5.0 with a confidence interval that does not include 1.0. The literature_pass packet's ai_classified_papers contains no paper classified as PS4. The reviewed variant-specific literature reports affected V30M patients and, in PMID:11409034, summarizes 14 homozygous affected patients and three asymptomatic carriers, but it does not provide a valid affected-versus-unaffected/population case-control table for this exact variant from which an OR and 95% CI can be calculated. Therefore PS4 cannot be adjudicated from the available evidence.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: 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.
No VCEP covers TTR, and vcep_materials.json contains no authoritative domain table. The available case evidence reports that this variant does not lie in a statistically significant hotspot, but it does not provide a residue-level, well-established critical functional-domain determination together with absence of benign variation. The generic PM1 requirements therefore cannot be evaluated completely from the supplied evidence.
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 target is TTR p.Val50Met. The supplied PM5 candidate artifact reports zero collected same-residue candidates but explicitly says classic same-residue PM5 semantics could not be confirmed safely and automatic harvesting was skipped. No independently documented different pathogenic missense substitution at TTR residue 50 is present in the supplied evidence, so PM5 cannot be adjudicated as met or not met.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The available evidence does not document an assumed de novo occurrence in a proband. In particular, there is no proband-specific parental testing or report establishing that the variant arose de novo without maternity and paternity confirmation. Therefore, PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
The evidence documents a disease-associated TTR missense variant and additional TTR missense disease reports, but it does not provide a gene-level assessment demonstrating both a low rate of benign missense variation and that missense variants are a common mechanism of disease under the generic PP2 rule. The single-variant gnomAD frequencies cannot establish the required gene-wide benign-missense rate.
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 governing PP4 rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The case materials identify TTR-related diseases associated with the variant but do not provide this patient's clinical phenotype, family history, or a sufficiently specific single-etiology diagnostic description. PP4 therefore cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available evidence. gnomAD v2.1 and v4.1 report zero homozygotes, but absence of homozygotes is not evidence that a healthy adult carried the variant. The retrieved variant-specific reports describe affected homozygous TTR Val30Met individuals, not healthy adults, and no qualifying healthy adult heterozygote, homozygote, or hemizygote observation with adequate age and phenotype ascertainment is documented. Because hereditary transthyretin amyloidosis is often late-onset and age-dependent, a healthy status would additionally require appropriate age and clinical ascertainment.
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.
No reviewed source provides a well-established in vitro or in vivo study showing that TTR Val30Met has no damaging effect on protein function or splicing. The available functional lead instead concerns disease-associated amyloid-related properties and does not support a benign functional conclusion. Because the evidence is insufficient to evaluate the benign functional criterion, BS3 is not assessed.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The evidence does not document an affected family member who lacks NM_000371.4:c.148G>A in an otherwise informative family. The extracted report of affected siblings homozygous for the variant is not a non-segregation observation, and the available record does not establish an informative affected non-carrier or exclude phenocopy and reduced penetrance. Therefore, BS4 is not assessed.
Lack of segregation in affected members of a family.
BP2 requires either observation in trans with a pathogenic variant in a fully penetrant dominant gene/disorder or observation in cis with a pathogenic variant. The case materials include a ClinVar citation titled as a compound heterozygote involving TTR Val30Met, but the cited article is not available for direct review here and the materials do not document parent testing, phase, the other allele's pathogenicity, or cis status. The available homozygous report also does not establish either BP2 configuration. BP2 therefore cannot be assessed reliably.
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 governing BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. The supplied case evidence does not identify an alternate pathogenic molecular diagnosis in the patient or a documented alternate molecular basis explaining the phenotype. BP5 therefore cannot be assessed.
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.148G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val50Met). 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 evaluated variant to be detected in trans with a pathogenic variant. The available variant-specific report documents homozygosity for TTR V30M, corresponding to NM_000371.4:c.148G>A / p.Val50Met, rather than a recessive disorder with a distinct pathogenic allele in trans. Therefore PM3 is not applicable to this TTR interpretation.
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.148G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val50Met). 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.148G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val50Met). 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.148G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val50Met). 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 individuals14 / 62,504 | 0.00022 |
| Middle Eastern1 / 6,062 | 0.00016 |
| Admixed American5 / 60,016 | 8.3e-05 |
| European (Finnish)4 / 64,014 | 6.2e-05 |
| European (non-Finnish)62 / 1,179,988 | 5.3e-05 |
| East Asian2 / 44,886 | 4.5e-05 |
| South Asian3 / 91,078 | 3.3e-05 |
| African/African American1 / 75,034 | 1.3e-05 |
| Remaining individuals3 / 6,140 | 0.00049 |
| European (non-Finnish)19 / 113,746 | 0.00017 |
| European (Finnish)2 / 21,648 | 9.2e-05 |
| Admixed American2 / 34,592 | 5.8e-05 |
This variant is present in gnomAD v4.1 (AF= 5.69978e-05; MAF= 0.00570%, 92/1614098 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000223986; MAF= 0.02240%, 14/62504 alleles, homozygotes = 0); grpmax FAF= 4.182e-05.
This variant is present in gnomAD v2.1 (AF= 0.000103395; MAF= 0.01034%, 26/251462 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000488599; MAF= 0.04886%, 3/6140 alleles, homozygotes = 0); grpmax FAF= 0.00010857.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, so the applicable computational path is REVEL only. REVEL is 0.711, meeting the generic PP3 supporting threshold of >= 0.644 but not the moderate threshold of >= 0.773 or the strong threshold of >= 0.932. Therefore PP3 is met at supporting strength.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, so the applicable computational path is REVEL only. REVEL is 0.711, which exceeds the generic BP4 supporting cutoff of <= 0.29 and is therefore not evidence for a tolerated effect. The SpliceAI score and BayesDel score are not used for BP4 in this missense situation.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
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.148G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val50Met). 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 = 0.711. BayesDel score = 0.499958.
10 paper records listed. 1 cited in the classification.
Homozygosity for the V30M was confirmed by RFLP and by mass spectrometry.
Location Results and discussion; Figure 1 and Table 1
Context Two Spanish siblings with familial amyloidotic polyneuropathy; TTR exon 2 SSCP analysis, NsiI RFLP analysis, and MALDI mass spectrometry of immunoprecipitated serum TTR peptides.
We report an amyloidogenic transthyretin (ATTR) Val30Met homozygote showing extremely early-onset, severe familial amyloid polyneuropathy (FAP).
Abstract
Randomization was performed in permuted blocks of 2 or 4 stratified for mutant TTR (non-V30M versus V30M) and study site.
Methods, Study Design
A genetically abnormal TTR may be involved in this disease.
Abstract
Pathologic findings in FAP TTR Met30 with onset before age 50 in relation to endemic foci (11 cases) were compared with those in 11 later-onset cases unrelated to endemic foci.
Abstract
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= 5.69978e-05; MAF= 0.00570%, 92/1614098 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000223986; MAF= 0.02240%, 14/62504 alleles, homozygotes = 0); grpmax FAF= 4.182e-05.
This variant is present in gnomAD v2.1 (AF= 0.000103395; MAF= 0.01034%, 26/251462 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000488599; MAF= 0.04886%, 3/6140 alleles, homozygotes = 0); grpmax FAF= 0.00010857.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (36 clinical laboratories) and as pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 13417)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.711. BayesDel score = 0.499958.
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.