ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2948G>A (p.Gly983Asp)

gnomAD frequency: 0.00003  dbSNP: rs766096031
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001842683 SCV001341554 uncertain significance Cardiac arrhythmia 2023-03-20 criteria provided, single submitter clinical testing This missense variant replaces glycine with aspartic acid at codon 983 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant causes an increase in sodium current (PMID: 27287068), however, clinical relevance of this observation is not known. This variant has been reported in an individual with unclear diagnosis but showing unusual T-wave (PMID: 27287068). This variant has been identified in 8/240764 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV003142105 SCV001414473 uncertain significance not provided 2024-11-12 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 983 of the SCN5A protein (p.Gly983Asp). This variant is present in population databases (rs766096031, gnomAD 0.007%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 36252119). ClinVar contains an entry for this variant (Variation ID: 919274). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 27287068). 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.
Ambry Genetics RCV002436737 SCV002749999 uncertain significance Cardiovascular phenotype 2022-07-05 criteria provided, single submitter clinical testing The p.G983D variant (also known as c.2948G>A), located in coding exon 16 of the SCN5A gene, results from a G to A substitution at nucleotide position 2948. The glycine at codon 983 is replaced by aspartic acid, an amino acid with similar properties. This alteration was reported in a subject with abnormal T waves who was noted to have a normal QTc interval. and functional studies by this group suggested gain of function (Ortiz-Bonnin B et al. Pflugers Arch, 2016 08;468:1375-87). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV003142105 SCV003821326 uncertain significance not provided 2022-12-19 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001842683 SCV004816698 uncertain significance Cardiac arrhythmia 2024-09-23 criteria provided, single submitter clinical testing This missense variant replaces glycine with aspartic acid at codon 983 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant causes an increase in sodium current (PMID: 27287068), however, clinical relevance of this observation is not known. This variant has been reported in an individual with unclear diagnosis but showing unusual T-wave (PMID: 27287068). This variant has been identified in 8/240764 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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