ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.2036C>A (p.Ser679Tyr) (rs777373322)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489053 SCV000577091 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing The S532Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S532Y variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S532Y 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001245310 SCV001418588 uncertain significance Holocarboxylase synthetase deficiency 2019-07-09 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 532 of the HLCS protein (p.Ser532Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. This variant is present in population databases (rs777373322, ExAC 0.003%). This variant has not been reported in the literature in individuals with HLCS-related disease. ClinVar contains an entry for this variant (Variation ID: 426609). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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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