ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.1721A>G (p.Asn574Ser) (rs201256776)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000490113 SCV000576940 uncertain significance not provided 2017-04-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SH3TC2 gene. The N574S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N574S variant is observed in 3/16,502 (0.02%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N574S 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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.
Illumina Clinical Services Laboratory,Illumina RCV000525499 SCV000454561 uncertain significance Charcot-Marie-Tooth disease type 4 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000310013 SCV000454562 uncertain significance Mononeuropathy of the Median Nerve 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000525499 SCV000657901 uncertain significance Charcot-Marie-Tooth disease type 4 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 574 of the SH3TC2 protein (p.Asn574Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs201256776, ExAC 0.02%). This variant has not been reported in the literature in individuals with SH3TC2-related disease. ClinVar contains an entry for this variant (Variation ID: 351913). 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: "Benign"; Align-GVGD: "Class C45"). 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.

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