ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.3550A>G (p.Met1184Val) (rs142451273)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000488069 SCV000279776 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SH3TC2 gene. The M1184V variant has been reported previously as a heterozygous variant in an individual with CMT1 who did not have a second identifiable variant in SH3TC2 and the authors concluded the pathogenicity of M1184V remains uncertain (Hoyer et al., 2014). The M1184V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. 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 RCV000403900 SCV000454518 uncertain significance Mononeuropathy of the Median Nerve 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000465654 SCV000454519 uncertain significance Charcot-Marie-Tooth disease type 4 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000465654 SCV000546365 uncertain significance Charcot-Marie-Tooth disease type 4 2018-10-13 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1184 of the SH3TC2 protein (p.Met1184Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs142451273, ExAC 0.06%). This variant has been reported in an individual who underwent genetic testing for Charcot-Marie-Tooth disease (PMID: 25614874). It has also been reported in the heterozygous state in an individual affected with Charcot-Marie-Tooth type 1 (PMID: 25025039). ClinVar contains an entry for this variant (Variation ID: 157532). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000488069 SCV000575444 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Dept. of Medical Genetics, Telemark Hospital Trust RCV000144878 SCV000172150 uncertain significance Charcot-Marie-Tooth disease 2013-11-01 no assertion criteria provided research

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