Submissions for variant NM_024577.4(SH3TC2):c.1973G>A (p.Arg658His)

gnomAD frequency: 0.00016  dbSNP: rs138040787

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197850	SCV000255068	uncertain significance	Charcot-Marie-Tooth disease type 4	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 658 of the SH3TC2 protein (p.Arg658His). This variant is present in population databases (rs138040787, gnomAD 0.02%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 216739). 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 with a negative predictive value of 95%. This variant disrupts the p.Arg658 amino acid residue in SH3TC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14574644, 16924012, 19744956, 21291453, 22462672). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Athena Diagnostics	RCV000713263	SCV000843852	uncertain significance	not provided	2017-12-20	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173828	SCV001336944	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
GeneDx	RCV000713263	SCV002028683	uncertain significance	not provided	2021-11-15	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain significance in a patient with Charcot-Marie-Tooth disease in the published literature; however, additional information was not provided (Volodarsky et al., 2021); 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: 32376792)
Mayo Clinic Laboratories, Mayo Clinic	RCV000713263	SCV002542143	uncertain significance	not provided	2021-07-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415856	SCV002723450	uncertain significance	Inborn genetic diseases	2021-12-22	criteria provided, single submitter	clinical testing	The p.R658H variant (also known as c.1973G>A), located in coding exon 11 of the SH3TC2 gene, results from a G to A substitution at nucleotide position 1973. The arginine at codon 658 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525900	SCV005040368	uncertain significance	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: SH3TC2 c.1973G>A (p.Arg658His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251060 control chromosomes. c.1973G>A has been reported in the literature in at-least one individual affected with Charcot-Marie Disease (example, Volodarsky_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Charcot-Marie Disease Type 4C. Additionally, one variant at the Arg658 residue has been reported as likely associated with disease in ClinVar (c.1972C>T p.Arg658Cys, ClinVar ID 21690), suggesting that this codon might be functionally important. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 216739). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV000713263	SCV005188667	uncertain significance	not provided		criteria provided, single submitter	not provided