ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.1529T>A (p.Val510Asp)

gnomAD frequency: 0.00002  dbSNP: rs769499327
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664908 SCV000788938 likely pathogenic Holocarboxylase synthetase deficiency 2017-01-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000664908 SCV001414570 pathogenic Holocarboxylase synthetase deficiency 2023-10-03 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 363 of the HLCS protein (p.Val363Asp). This variant is present in population databases (rs769499327, gnomAD 0.02%). This missense change has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 8817339, 19806568; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550218). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HLCS protein function. Experimental studies have shown that this missense change affects HLCS function (PMID: 10068510, 10590022). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000664908 SCV004028690 pathogenic Holocarboxylase synthetase deficiency 2023-07-20 criteria provided, single submitter clinical testing Variant summary: HLCS c.1088T>A (p.Val363Asp) results in a non-conservative amino acid change in 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 1.6e-05 in 251476 control chromosomes (gnomAD). c.1088T>A has been reported in the literature in individuals affected with Holocarboxylase Synthetase Deficiency (examples: Dupuis_1996, Wang_2009, and Esparza_2011). These data indicate that the variant is likely to be associated with disease. Multiple experimental studies have shown that this missense change affects normal protein activity (example: Dupuis_1999 and Sakamoto_1999). The following publications have been ascertained in the context of this evaluation (PMID: 8817339, 10068510, 21615476, 10590022, 19695181). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000664908 SCV004199859 pathogenic Holocarboxylase synthetase deficiency 2023-03-23 criteria provided, single submitter clinical testing

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