Submissions for variant NM_000371.4(TTR):c.421GTC[1] (p.Val142del)

dbSNP: rs121918096

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014402	SCV000696633	pathogenic	Familial amyloid neuropathy	2016-08-16	criteria provided, single submitter	clinical testing	Variant summary: The TTR c.424_426delGTC (p.Val142del) variant causes an in-frame deletion in the last exon. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals including a large family in which the variant segregates with disease (Munar-Ques_2001). The variant of interest has been classified as pathogenic/likely pathogenic by multiple reputable databases/clinical laboratories. Therefore, the variant of interest has been classified as Pathogenic.
Invitae	RCV000014402	SCV001410440	pathogenic	Familial amyloid neuropathy	2023-12-20	criteria provided, single submitter	clinical testing	This variant, c.424_426del, results in the deletion of 1 amino acid(s) of the TTR protein (p.Val142del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 9191784, 11140845, 24101130). It has also been observed to segregate with disease in related individuals. This variant is also known as deltaV122. ClinVar contains an entry for this variant (Variation ID: 13460). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TTR function (PMID: 15820680). This variant disrupts the p.Val142 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12050338, 15820680, 17503405, 18276611, 19781421, 22745357, 24184229, 25846356). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000014402	SCV000034651	pathogenic	Familial amyloid neuropathy	2000-11-01	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000014402	SCV000060032	likely pathogenic	Familial amyloid neuropathy	2008-09-02	no assertion criteria provided	clinical testing