ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.113A>G (p.Asp38Gly)

dbSNP: rs121918098
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000036373 SCV000060025 pathogenic Amyloidosis, hereditary systemic 1 2012-03-01 criteria provided, single submitter clinical testing The Asp38Gly variant (TTR) has been identified in 4 individuals with leptomening eal/CNS-related TTR amyloidosis, including one individual with restrictive cardi omyopathy (note, the variant is also referred to as Asp18Gly; Vidal 1996, Jin 20 04, Barreiros 2010). In addition, this variant segregates with disease in 4 affe cted family members, including one obligate carrier, and was absent from 80 cont rol chromosomes (Vidal 1996, Jin 2004). Furthermore, functional analyses showed the Asp38Gly variant results in an abnormal protein that is highly destabilized, has diminished secretion, and has abnormal cellular localization (Hammarstrom 2 003, Sekijima 2005). In summary, the Asp38Gly variant is highly likely to be pat hogenic based upon correlation with clinical phenotype, segregation with disease , and functional studies.
Labcorp Genetics (formerly Invitae), Labcorp RCV000036373 SCV002119879 pathogenic Amyloidosis, hereditary systemic 1 2021-05-25 criteria provided, single submitter clinical testing Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp38 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23126592, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 8579098, 20209591). It has also been observed to segregate with disease in related individuals. This variant is also known as D18G. ClinVar contains an entry for this variant (Variation ID: 13463). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 38 of the TTR protein (p.Asp38Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine.
OMIM RCV000036373 SCV000034654 pathogenic Amyloidosis, hereditary systemic 1 1996-12-01 no assertion criteria provided literature only

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