ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.355G>A (p.Asp119Asn)

gnomAD frequency: 0.00006  dbSNP: rs76410435
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000756859 SCV000209362 likely benign not provided 2020-12-08 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21406045, 30683924, 32376792)
Invitae RCV000697928 SCV000826562 uncertain significance Familial amyloid neuropathy 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 119 of the TTR protein (p.Asp119Asn). This variant is present in population databases (rs76410435, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of TTR-related conditions (PMID: 32376792, 34658264; Invitae). This variant is also known as D99N. ClinVar contains an entry for this variant (Variation ID: 181690). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TTR function (PMID: 21406045). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756859 SCV000884816 likely benign not provided 2017-12-20 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000697928 SCV001283900 likely benign Familial amyloid neuropathy 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Molecular Genetics Laboratory, London Health Sciences Centre RCV001173299 SCV001336383 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Ambry Genetics RCV002336372 SCV002618826 likely benign Cardiovascular phenotype 2020-01-23 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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