ClinVar Miner

Submissions for variant NM_000411.8(HLCS):c.1648G>A (p.Val550Met) (rs119103231)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001988 SCV000796718 likely pathogenic Holocarboxylase synthetase deficiency 2017-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000185961 SCV000238919 pathogenic not provided 2016-09-27 criteria provided, single submitter clinical testing The V550M missense mutation in the HLCS gene has been reported previously in association with holocarboxylase synthetase (HLCS) deficiency (Dupuis et al., 1996). V550M is located in the biotin-binding domain of the holocarboxylase synthetase enzyme (Dupuis et al.,1996).The variant is found in HLCS panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000001988 SCV000919520 pathogenic Holocarboxylase synthetase deficiency 2018-11-19 criteria provided, single submitter clinical testing Variant summary: HLCS c.1648G>A (p.Val550Met) results in a conservative amino acid change located in the Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL) catalytic domain (IPR004143) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246272 control chromosomes (gnomAD). c.1648G>A has been reported in the literature in homo- or heterozygous state, in multiple individuals from several ethnic groups who were affected with Holocarboxylase Synthetase Deficiency (see e.g. Dupuis 1996, Yang 2001, Tang 2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity, and the enzyme activity was moderately biotin responsive (Dupuis 1999). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic (1x)/likely pathogenic(1x). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001988 SCV000022146 pathogenic Holocarboxylase synthetase deficiency 2001-11-01 no assertion criteria provided literature only

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