Submissions for variant NM_001365536.1(SCN9A):c.1154T>G (p.Val385Gly)

gnomAD frequency: 0.00001  dbSNP: rs202159091

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000805496	SCV000945454	uncertain significance	Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7	2022-12-06	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 650356). This variant is present in population databases (rs202159091, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 385 of the SCN9A protein (p.Val385Gly).
GeneDx	RCV001796238	SCV002032828	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing	The V385G variant has been previously identified in a patient with multiple anomalies including microcephaly, developmental delay, seizures and features suggestive of Cornelia de Lange syndrome who also harbored a likely causative variant in the SMC1A gene (Hansen et al., 2013); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23863341)
Ambry Genetics	RCV002360974	SCV002625391	uncertain significance	Inborn genetic diseases	2019-12-18	criteria provided, single submitter	clinical testing	The p.V385G variant (also known as c.1154T>G), located in coding exon 9 of the SCN9A gene, results from a T to G substitution at nucleotide position 1154. The valine at codon 385 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003411776	SCV004114083	uncertain significance	SCN9A-related condition	2023-01-12	criteria provided, single submitter	clinical testing	The SCN9A c.1154T>G variant is predicted to result in the amino acid substitution p.Val385Gly. This variant was reported as a variant of uncertain significance in an individual with suspected Cornelia de Lange syndrome in whom a de novo SMC1A splice variant was also found (Hansen J et al. 2013. PubMed ID: 23863341). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-167145107-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.