Submissions for variant NM_024577.3(SH3TC2):c.2990G>A (p.Arg997Gln) (rs140307699)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000233589	SCV000290776	uncertain significance	Charcot-Marie-Tooth disease type 4	2019-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 997 of the SH3TC2 protein (p.Arg997Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs140307699, ExAC 0.04%) but has not been reported in the literature in individuals with a SH3TC2-related disease. ClinVar contains an entry for this variant (Variation ID: 241504). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000519691	SCV000621426	uncertain significance	not specified	2017-10-06	criteria provided, single submitter	clinical testing	The R997Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R997Q variant is observed in 8/10,150 (0.08%) alleles from individuals of Ashkenazi Jewish background (Lek et al., 2016). The R997Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated 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.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001173825	SCV001336940	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing

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