Variant classification summary

NM_000371.4:c.424G>A

TTR · NP_000362.1:p.(Val142Ile) · NM_000371.4

GRCh37: chr18:29178618 G>A · GRCh38: chr18:31598655 G>A

Gene: TTR Transcript: NM_000371.4

Final call

Pathogenic

PS3 strong PS4 strong PM5 moderate PP3 supporting BP5 supporting

Variant details

Gene

TTR

Transcript

NM_000371.4

Protein

NP_000362.1:p.(Val142Ile)

gnomAD AF

0.000887811152097601 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong—independent assays demonstrated impaired TTR stability and increased amyloidogenic aggregation.

2

Pathogenic: PS4 strong—case-control data yielded OR 9.08 (95% CI 2.35–35.03).

3

Pathogenic: PM5 moderate—pathogenic or likely pathogenic missense changes occur at Val142.

4

Pathogenic: PP3 supporting—REVEL 0.645 meets the 0.644 threshold.

5

Benign-direction evidence: BP5 supporting—four AL amyloidosis patients also carried V122I, an alternate molecular basis.

Final determination: Under the generic ACMG/AMP fallback, two strong pathogenic criteria satisfy the Pathogenic rule; the additional moderate and supporting pathogenic criteria reinforce the call, while BP5 alone does not satisfy a benign rule.

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	Not met	Not met: ClinVar documents the same c.424G>A change, but no alternate nucleotide producing p.Val142Ile is established.	clinvar PMID:35903975
PS2	Not assessed	Not assessed: no documented proband case demonstrates confirmed maternity and paternity with the variant absent from both parents.	clinvar
PS3	Met	Met, strong: two independent assays showed impaired TTR stability and aggregation, including threefold faster tetramer dissociation and turbidity 0.241 versus 0.046 AU (p<0.0001).	PMID:11752443 PMID:35903975
PS4	Met	Met: affected/control counts yielded OR 9.08 (95% CI 2.35-35.03), satisfying the PS4 requirement of OR >5.0 with a confidence interval excluding 1.0.	PMID:22877808
PM1	Not assessed	Not assessed: no hotspot was found, and no authoritative TTR critical-domain entry or independent evidence establishes Val142 as a qualifying domain residue.
PM2	Not met	Not met: gnomAD v4.1 overall AF 0.000887811 exceeds the 0.0001 PM2 threshold.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: TTR V122I disease is represented in affected patients as heterozygous, not as a recessive disorder requiring a pathogenic variant in trans.	PMID:25741868 PMID:22877808
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	Met	Met at moderate strength: ClinVar documents pathogenic p.Val142Ala and likely pathogenic p.Val142Leu at the same residue.	clinvar
PM6	Not assessed	Not assessed: no documented assumed-de novo proband has the variant absent from tested parents without confirmed parentage.	clinvar
PP1	Not assessed	Not assessed: no citable pedigree provides genotypes, affected relatives, and informative meioses for this variant.
PP2	Not assessed	Not assessed: the case lacks a documented low benign-missense rate for TTR, despite missense disease mechanism evidence.	PMID:11752443 clinvar
PP3	Met	Met at supporting: missense REVEL 0.645 meets the supplied PP3 supporting threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: no patient-specific phenotype or family-history description is available to determine whether the presentation is highly specific for a single-gene disease.
PP5	Not met	Not met: exact-variant ClinVar has zero expert-panel submissions, so ordinary laboratory and aggregate pathogenic labels cannot trigger PP5.	clinvar PMID:22877808
BA1	Not met	Not met: gnomAD v4.1 overall AF 0.000887811 is below the 0.05 BA1 threshold.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not assessed	Not assessed: African/African American AF 0.0169693 exceeds 1%, but no maximum-credible-frequency inputs account for TTR Val142Ile’s late-onset ancestry-specific context.	gnomad_v4 gnomad_v2 PMID:22877808
BS2	Not assessed	Not assessed: gnomAD v4.1 reports 8 homozygotes, but this does not establish healthy adult status or early full penetrance.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: variant-specific assays showed damaging effects, including threefold faster tetramer dissociation and significantly greater aggregation than wild-type TTR.	PMID:11752443 PMID:35903975
BS4	Not assessed	Not assessed: no documented affected relatives lacking the variant establish informative familial non-segregation.
BP1	Not met	Not met: TTR evidence centers on amyloidogenic missense disease, not a gene pattern dominated by truncating variants.	PMID:11752443 PMID:35903975
BP2	Not assessed	Not assessed: no affected-proband or family data establish a second pathogenic TTR variant in trans or cis with c.424G>A.	PMID:25741868
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: missense REVEL 0.645 exceeds the supplied BP4 supporting threshold of <=0.29.	revel
BP5	Met	Met: four patients with AL amyloidosis, an alternate molecular basis, also carried the TTR V122I allele.
BP6	Not met	Not met: exact-variant ClinVar has zero expert-panel submissions and no expert-panel benign or likely-benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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