Submissions for variant NM_024577.4(SH3TC2):c.3433G>T (p.Ala1145Ser)

dbSNP: rs141715248

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000340541	SCV000454520	uncertain significance	Charcot-Marie-Tooth disease type 4C	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000403282	SCV000454521	uncertain significance	Susceptibility to mononeuropathy of the median nerve, mild	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001343959	SCV001537984	uncertain significance	Charcot-Marie-Tooth disease type 4	2022-08-16	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt SH3TC2 protein function. ClinVar contains an entry for this variant (Variation ID: 351898). This variant has not been reported in the literature in individuals affected with SH3TC2-related conditions. This variant is present in population databases (rs141715248, gnomAD 0.004%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1145 of the SH3TC2 protein (p.Ala1145Ser).
Ambry Genetics	RCV002450927	SCV002614780	uncertain significance	Inborn genetic diseases	2021-08-15	criteria provided, single submitter	clinical testing	The p.A1145S variant (also known as c.3433G>T), located in coding exon 15 of the SH3TC2 gene, results from a G to T substitution at nucleotide position 3433. The alanine at codon 1145 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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.
CeGaT Center for Human Genetics Tuebingen	RCV003430903	SCV004157308	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	SH3TC2: PM2
Athena Diagnostics	RCV003430903	SCV004230065	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.