Submissions for variant NM_001352514.2(HLCS):c.2089G>A (p.Val697Met)

dbSNP: rs119103231

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001988	SCV001236126	pathogenic	Holocarboxylase synthetase deficiency	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 550 of the HLCS protein (p.Val550Met). This variant is present in population databases (rs119103231, gnomAD 0.003%). This missense change has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 9396568, 10068510, 12124727, 12633764, 24099927). 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: 1911). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HLCS function (PMID: 9396568, 10068510). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000001988	SCV004199854	pathogenic	Holocarboxylase synthetase deficiency	2024-03-19	criteria provided, single submitter	clinical testing
OMIM	RCV000001988	SCV000022146	pathogenic	Holocarboxylase synthetase deficiency	2001-11-01	no assertion criteria provided	literature only
Counsyl	RCV000001988	SCV000796718	likely pathogenic	Holocarboxylase synthetase deficiency	2017-12-22	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000001988	SCV001456936	pathogenic	Holocarboxylase synthetase deficiency	2020-09-16	no assertion criteria provided	clinical testing