ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.2182G>A (p.Gly728Ser) (rs119103230)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000001987 SCV000756234 pathogenic Holocarboxylase synthetase deficiency 2020-05-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 581 of the HLCS protein (p.Gly581Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs119103230, ExAC 0.003%). This variant has been observed as homozygous or in combination with another HLCS variant in individuals affected with holocarboxylase synthetase deficiency (PMID: 10190325, 12124727). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1910). This variant has been reported to affect HLCS protein function (PMID: 10190325, 24239178, 10590022). 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.
OMIM RCV000001987 SCV000022145 pathogenic Holocarboxylase synthetase deficiency 2001-11-01 no assertion criteria provided literature only

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