ClinVar Miner

Submissions for variant NM_024577.3(SH3TC2):c.3166C>T (p.Leu1056Phe) (rs201805333)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235844 SCV000294152 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing The L1056F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. However, the L1056F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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.
Invitae RCV000473334 SCV000546366 uncertain significance Charcot-Marie-Tooth disease type 4 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1056 of the SH3TC2 protein (p.Leu1056Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs201805333, ExAC 0.01%) but has not been reported in the literature in individuals with a SH3TC2-related disease. ClinVar contains an entry for this variant (Variation ID: 246560). 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 C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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