Submissions for variant NM_024577.4(SH3TC2):c.1000A>G (p.Met334Val)

dbSNP: rs139653980

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000728925	SCV000294188	uncertain significance	not provided	2016-05-24	criteria provided, single submitter	clinical testing	The c.1000 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Several in-silico splice prediction models predict c.1000 A>G damages the natural splice donor site of intron 8 and may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.1000 A>G does not affect splicing, it will result in the M334V missense variant. The M334V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts the M334V variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Eurofins Ntd Llc (ga)	RCV000728925	SCV000856551	uncertain significance	not provided	2017-09-07	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174028	SCV001337148	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001689763	SCV001911520	likely pathogenic	Tip-toe gait	2021-04-02	criteria provided, single submitter	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
Ambry Genetics	RCV002460063	SCV002618053	uncertain significance	Inborn genetic diseases	2020-02-03	criteria provided, single submitter	clinical testing	The p.M334V variant (also known as c.1000A>G), located in coding exon 8 of the SH3TC2 gene, results from an A to G substitution at nucleotide position 1000. The methionine at codon 334 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519835	SCV003271123	uncertain significance	Charcot-Marie-Tooth disease type 4	2022-06-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 334 of the SH3TC2 protein (p.Met334Val). This variant is present in population databases (rs139653980, gnomAD 0.02%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease type 4C (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 246592). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387818	SCV004100066	uncertain significance	not specified	2023-09-21	criteria provided, single submitter	clinical testing	Variant summary: SH3TC2 c.1000A>G (p.Met334Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 5' donor site. Four predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251336 control chromosomes (gnomAD). c.1000A>G has been reported in the literature in an individual suspected of having Charcot-Marie Disease (Volodarsky_2021). This report does not provide unequivocal conclusions about association of the variant with Charcot-Marie Disease Type 4C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32376792). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004529417	SCV004105439	uncertain significance	SH3TC2-related disorder	2023-09-02	criteria provided, single submitter	clinical testing	The SH3TC2 c.1000A>G variant is predicted to result in the amino acid substitution p.Met334Val. This variant was reported in an individual with Charcot-Marie-Tooth disease as variant of uncertain significance (Table S2, Volodarsky et al. 2021. PubMed ID: 32376792). This variant was also found in an individual with Charcot-Marie-Tooth 4C in addition to two causative variants and therefore was assessed as likely not of clinical concern (Rehbein et al. 2023. PubMed ID: 36947133). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-148417859-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.