ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.2182G>A (p.Gly728Ser)

gnomAD frequency: 0.00001  dbSNP: rs119103230
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000001987 SCV000756234 pathogenic Holocarboxylase synthetase deficiency 2024-10-17 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 581 of the HLCS protein (p.Gly581Ser). This variant is present in population databases (rs119103230, gnomAD 0.006%). This missense change has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 10190325, 12124727). 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: 1910). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HLCS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HLCS function (PMID: 10190325, 10590022, 24239178). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000001987 SCV000996255 pathogenic Holocarboxylase synthetase deficiency 2019-03-01 criteria provided, single submitter clinical testing This variant has been reported as homozygous or compound heterozygous in individuals affected with holocarboxylase synthetase deficiency (PMID: 10190325, 12124727, 11735028), and classified in the ClinVar database as Pathogenic (Variation ID: 1910). Experimental studies have shown that this missense change reduces HLCS enzymatic activity in vitro (PMID: 10190325, 24239178). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/246262) and thus is presumed to be rare. The c.1741G>A, p.Gly581Ser variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1741G>A, p.Gly581Ser variant is classified as Pathogenic.
Baylor Genetics RCV000001987 SCV004199824 pathogenic Holocarboxylase synthetase deficiency 2024-03-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000001987 SCV005664088 likely pathogenic Holocarboxylase synthetase deficiency 2024-04-23 criteria provided, single submitter clinical testing
OMIM RCV000001987 SCV000022145 pathogenic Holocarboxylase synthetase deficiency 2001-11-01 no assertion criteria provided literature only
Natera, Inc. RCV000001987 SCV002083721 pathogenic Holocarboxylase synthetase deficiency 2020-11-05 no assertion criteria provided clinical testing

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