Submissions for variant NM_024577.3(SH3TC2):c.794C>T (p.Ser265Phe) (rs149873249)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520448	SCV000619440	uncertain significance	not provided	2017-07-25	criteria provided, single submitter	clinical testing	The S265F variant in the SH3TC2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. While not present in the homozygous state, this variant is observed in 12/10406 (0.11%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The S265F 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 not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S265F as a variant of uncertain significance.
Invitae	RCV000654163	SCV000776053	uncertain significance	Charcot-Marie-Tooth disease type 4	2017-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine with phenylalanine at codon 265 of the SH3TC2 protein (p.Ser265Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs149873249, ExAC 0.1%). This variant has not been reported in the literature in individuals with SH3TC2-related disease. 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 C25"). 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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