ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.2975T>C (p.Val992Ala) (rs1057524814)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000429418 SCV000536527 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN9A gene. The V981A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V981A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a conserved position predicted to be within the cytoplasmic loop between second and third homologous domains. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V981A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV001249706 SCV001423730 uncertain significance SCN9A-related disorders 2019-11-05 criteria provided, single submitter clinical testing The SCN9A c.2942T>C (p.Val981Ala) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The p.Val981Ala variant is not found in Genome Aggregation Database, however this was noted to be a region with reduced sequence coverage. The p.Val981Ala variant occurs at a conserved residue in the cytoplasmic topological domain between the second and third homologous domain of the associated protein, Nav1.7. Based on the limited evidence, the p.Val981Ala variant is classified as a variant of unknown significance for SCN9A-related disorders.
Invitae RCV001344028 SCV001538056 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2020-08-29 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 981 of the SCN9A protein (p.Val981Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 393158). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). 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. 5

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