ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.751C>T (p.Pro251Ser) (rs144963732)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416281 SCV000493515 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing
GeneDx RCV000416281 SCV000536098 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SH3TC2 gene. The P251S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P251S variant is observed in 17/66,674 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P251S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. 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.
Invitae RCV000654078 SCV000775968 uncertain significance Charcot-Marie-Tooth disease type 4 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 251 of the SH3TC2 protein (p.Pro251Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs144963732, ExAC 0.03%). This variant has not been reported in the literature in individuals with SH3TC2-related disease. ClinVar contains an entry for this variant (Variation ID: 374659). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000416281 SCV000886107 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing The SH3TC2 c.751C>T; p.Pro251Ser variant (rs144963732), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.04% (identified on 48 out of 126,674 chromosomes). The proline at position 251 is highly conserved, considering 8 species, and computational analyses of the effects of the p.Pro251Ser variant on protein structure and function make conflicting predictions (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Based on all available evidence, the clinical significance of the p.Pro251Ser variant cannot be determined with certainty.

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