Variant classification summary

NM_000371.4:c.148G>A

TTR · NP_000362.1:p.(Val50Met) · NM_000371.4

GRCh37: chr18:29172937 G>A · GRCh38: chr18:31592974 G>A

Gene: TTR Transcript: NM_000371.4

Final call

Likely Pathogenic

PS1 strong PM2 supporting PP1 supporting PP3 supporting

Variant details

Gene

TTR

Transcript

NM_000371.4

Protein

NP_000362.1:p.(Val50Met)

gnomAD AF

5.699777832572743e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS1 strong reflects the exact TTR Val50Met change reported in affected individuals.

2

Likely Pathogenic: PM2 supporting reflects the very low gnomAD v4.1 filtering grpmax FAF of 0.00004182.

3

Likely Pathogenic: PP1 supporting reflects segregation in more than 100 affected individuals across more than 95 families.

4

Likely Pathogenic: PP3 supporting reflects REVEL 0.711 under the adjudicated missense calibration.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus at least two supporting pathogenic criteria yields Likely Pathogenic; PS1 strong, PM2 supporting, PP1 supporting, and PP3 supporting satisfy this 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	Met	Met: the exact TTR Val50Met change is reported in affected siblings with familial amyloidotic polyneuropathy and confirmed by RFLP and mass spectrometry.	PMID:11409034
PS2	Not assessed	Not assessed: no proband-specific parental testing confirms both maternity and paternity, and no documented absence of family history is available.
PS3	Not assessed	Not assessed: PMID:6736244 supports altered TTR amyloid-related properties, but validated assay controls and a permitted PS3 strength threshold are unavailable.	PMID:6736244
PS4	Not assessed	Not assessed: no valid affected-versus-control counts or odds ratio with a 95% confidence interval are available for exact TTR c.148G>A.	PMID:11409034 gnomad_v4
PM1	Not assessed	Not assessed: no authoritative critical-domain annotation or benign-variation exclusion is available for TTR Val50Met, and the hotspot result is negative.	hotspots
PM2	Met	Met at supporting strength: gnomAD v4.1 grpmax FAF is 0.00004182, below the 0.0001 PM2 supporting threshold.	gnomad_v4
PM3	N/A	Not applicable: PM3 requires a recessive disorder with the variant detected in trans, whereas the report documents homozygous TTR V30M rather than a qualifying trans pathogenic allele.	PMID:11409034
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 independently documented pathogenic alternative missense change at TTR residue 50 is available in the supplied evidence.	pm5_candidates
PM6	Not assessed	Not assessed: no proband-specific evidence establishes that NM_000371.4:c.148G>A was assumed de novo without parental confirmation.
PP1	Met	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.	clinvar PMID:11940682
PP2	Not assessed	Not assessed: TTR disease-associated missense reports are present, but no gene-wide benign-missense rate establishes the full PP2 requirement.	PMID:11409034 gnomad_v4
PP3	Met	Met at supporting strength: REVEL 0.711 meets the PP3 threshold of >=0.644 but is below the moderate threshold of >=0.773.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not supplied, so phenotype specificity for a single genetic etiology cannot be judged.	clinvar
PP5	Not met	Not met: ClinVar shows zero expert-panel submissions for exact TTR c.148G>A, despite ordinary Pathogenic and Likely pathogenic submissions.	clinvar PMID:18506713 PMID:15249622
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00004182, substantially below the 0.05 stand-alone benign threshold.	gnomad_v4 clinvar
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00004182, below the generic BS1 default threshold of 0.01.	gnomad_v4
BS2	Not assessed	Not assessed: no qualifying healthy adult carrier is documented, and gnomAD reports zero homozygotes rather than a healthy-observation result.	gnomad_v2 gnomad_v4 PMID:11409034
BS3	Not assessed	Not assessed: no reviewed assay shows that TTR Val30Met has no damaging effect on protein function or splicing.
BS4	Not assessed	Not assessed: no informative affected non-carrier is documented, and the reported affected homozygous siblings do not demonstrate lack of segregation.	PMID:11409034
BP1	Not met	Not met: available TTR disease evidence centers on pathogenic missense variation, not a gene mechanism primarily involving truncating variants.	PMID:11409034
BP2	Not assessed	Not assessed: phase, parent testing, and a qualifying cis or trans pathogenic allele are not documented, so neither BP2 pathway can be verified.	clinvar PMID:11409034
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 0.711 is above the <=0.29 BP4 supporting cutoff for missense variants.	revel
BP5	Not assessed	Not assessed: no alternate pathogenic molecular basis is documented for the case in which TTR c.148G>A was found.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification for TTR c.148G>A.	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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