ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.2585A>C (p.Asp862Ala)

gnomAD frequency: 0.00001  dbSNP: rs752737867
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001779097 SCV002015013 uncertain significance not specified 2021-10-22 criteria provided, single submitter clinical testing Variant summary: HLCS c.2144A>C (p.Asp715Ala) results in a non-conservative amino acid change located in the Biotin protein ligase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251098 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2144A>C in individuals affected with Holocarboxylase Synthetase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. A different variant affecting the same codon (p.D715G) has been reported to associate with Holocarboxylase synthetase deficiency (PMID 16134170). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000990348 SCV003276587 uncertain significance Holocarboxylase synthetase deficiency 2021-09-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 715 of the HLCS protein (p.Asp715Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs752737867, ExAC 0.005%). This variant has not been reported in the literature in individuals with HLCS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics RCV000990348 SCV001141293 likely pathogenic Holocarboxylase synthetase deficiency 2019-05-28 flagged submission clinical testing

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