Variant classification summary

NM_000371.4:c.238A>G

TTR · NP_000362.1:p.(Thr80Ala) · NM_000371.4

GRCh37: chr18:29175120 A>G · GRCh38: chr18:31595157 A>G

Gene: TTR Transcript: NM_000371.4

Final call

Likely Pathogenic

PS1 strong PS3 supporting PM2 supporting PP1 supporting PP3 supporting

Variant details

Gene

TTR

Transcript

NM_000371.4

Protein

NP_000362.1:p.(Thr80Ala)

gnomAD AF

1.672800267648043e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS1 strong establishes the same pathogenic p.Thr80Ala change.

2

Likely Pathogenic: PS3 supporting shows altered variant-specific TTR biochemical behavior.

3

Likely Pathogenic: PM2 supporting shows an ultralow gnomAD allele frequency of 1.6728e-05.

4

Likely Pathogenic: PP1 supporting reports the variant in affected relatives from familial TTR amyloidosis kindreds.

5

Likely Pathogenic: PP3 supporting reflects REVEL 0.675 above the adjudicated missense threshold of 0.644.

Final determination: Under the generic ACMG/AMP 2015 fallback, one Strong pathogenic criterion plus four Supporting pathogenic criteria satisfies Likely Pathogenic; no benign rule is satisfied.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met: the exact TTR p.Thr80Ala change is established as pathogenic in ClinVar and reported independently as the mature-protein T60A/A60 variant.	clinvar PMID:15185492 PMID:24368466 spliceai
PS2	Not assessed	Not assessed: no documented maternity and paternity confirmation, parental variant-negative testing, and absence of family history for a de novo proband.
PS3	Met	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.	PMID:15185492 PMID:3097057
PS4	Not met	Not met: affected-case reports lack a matched control comparison, so the required OR/RR >5.0 with a confidence interval excluding 1.0 cannot be established.	PMID:24368466 PMID:15185492 PMID:3097057 gnomad_v4
PM1	Not assessed	Not assessed: no authoritative TTR hotspot or critical-domain annotation with supporting absence of benign variation was supplied for residue 80.	hotspots cosmic
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 1.6728e-05, below the PM2 threshold of 0.0001, with 0 homozygotes.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: PM3 is limited to recessive disorders, whereas TTR hereditary amyloidosis is described as autosomal dominant.	PMID:3722385
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense change at TTR residue 80 (mature residue 60) was confirmed in the supplied evidence.	pm5_candidates PMID:15185492 PMID:24368466
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence or parental testing for NM_000371.4:c.238A>G in the proband.
PP1	Met	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.	PMID:2122246 PMID:3722385
PP2	Not assessed	Not assessed: TTR missense disease mechanism is supported, but no defined gene-level measure shows a low rate of benign missense variation.	PMID:15185492 PMID:24368466 clinvar
PP3	Met	Met: REVEL 0.675 exceeds the generic PP3 supporting threshold of >=0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not provided, so phenotype specificity for a single-gene disease cannot be judged.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel classification, and the supporting publications are available for independent evaluation rather than unavailable evidence.	clinvar PMID:3722385
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.107e-05, below the generic BA1 threshold of 0.05, and the 0.000112022 popmax estimate is not used.	gnomad_v4 clinvar
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.107e-05, far below the generic BS1 default of 0.01, with no frequency evidence suggesting excess prevalence.	gnomad_v4 gnomad_v2 PMID:3722385
BS2	Not assessed	Not assessed: gnomAD has 0 homozygotes, but its unphenotyped carriers cannot establish healthy adulthood for this autosomal-dominant late-onset disorder.	gnomad_v2 gnomad_v4 PMID:3722385
BS3	Not met	Not met: one assay found no significant binding change, but recombinant TTR showed 86.2% binding and 100% aggregation at pH 4.8.	PMID:15185492 PMID:3097057
BS4	Not assessed	Not assessed: no affected family members are documented as variant-negative, so lack of segregation cannot be established.
BP1	Not met	Not met: available TTR disease evidence centers on recurrent pathogenic missense substitutions and amyloidogenic protein behavior, not primarily truncating variants.	PMID:15185492 PMID:24368466
BP2	Not assessed	Not assessed: no second pathogenic variant or parental/offspring phase data establish cis or trans configuration for BP2.	PMID:3722385
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.675 is above the generic BP4 supporting cutoff of <=0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no case is documented with both this variant and a confirmed alternate molecular basis for the disease.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign classification exists, and the available literature is not an unavailable benign-source assertion.	clinvar PMID:3722385 PMID:24368466
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.