Submissions for variant NM_001352514.2(HLCS):c.1088T>G (p.Leu363Arg)

gnomAD frequency: 0.00001  dbSNP: rs28934602

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000001991	SCV000792879	likely pathogenic	Holocarboxylase synthetase deficiency	2017-07-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001991	SCV001236730	pathogenic	Holocarboxylase synthetase deficiency	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 216 of the HLCS protein (p.Leu216Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with holocarboxylase synthetase deficiency (HCS) (PMID: 8817339, 24085707). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1914). 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: 21894551, 22027809). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001991	SCV002571987	pathogenic	Holocarboxylase synthetase deficiency	2022-08-12	criteria provided, single submitter	clinical testing	Variant summary: HLCS c.647T>G (p.Leu216Arg) 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 was absent in 251278 control chromosomes. c.647T>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Holocarboxylase Synthetase Deficiency (example, Dupuis_1996, Morrone_2002, Slavin_2014). These data indicate that the variant is very likely to be associated with disease. At least two publications report concordant experimental evidence evaluating an impact on protein function (example, Sakamoto_1999, Bailey_2008). The most pronounced variant effect results in severaly decreased (0.6% of WT) maximal velocity imacting Holocarboxylase synthetase enzyme activity in vitro. This severely compromised in-vitro activity could not be restored by additional biotin (Bailey_2008). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000001991	SCV004199856	pathogenic	Holocarboxylase synthetase deficiency	2023-04-13	criteria provided, single submitter	clinical testing
OMIM	RCV000001991	SCV000022149	pathogenic	Holocarboxylase synthetase deficiency	2002-07-22	no assertion criteria provided	literature only
Natera, Inc.	RCV000001991	SCV002083740	pathogenic	Holocarboxylase synthetase deficiency	2020-07-02	no assertion criteria provided	clinical testing