Submissions for variant NM_001352514.2(HLCS):c.1223del (p.Gly408fs)

dbSNP: rs771944310

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185969	SCV000238927	pathogenic	not provided	2024-05-20	criteria provided, single submitter	clinical testing	Also known as delG1067; This variant is associated with the following publications: (PMID: 7842009, 35314707, 8541348, 11735028, 29961769, 9870216, 33514801)
Illumina Laboratory Services, Illumina	RCV000410410	SCV000915952	pathogenic	Holocarboxylase synthetase deficiency	2017-04-28	criteria provided, single submitter	clinical testing	The HLCS c.782delG (p.Gly261ValfsTer20) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Gly261ValfsTer20 variant, described as one of the most common variants in the Japanese population in individuals with holocarboxylase synthetase (HLCS) deficiency, has been reported in three studies in which it is found in a total of nine patients with HLCS deficiency including in eight in a compound heterozygous state (of whom two are siblings) and in one in a heterozygous state in whom a second allele could not be identified based on screening of five variants (Suzuki et al. 1994; Yang et al. 2000; Yang et al. 2001; Castro et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. Enzyme activity in patients ranged between 5-14% of the enzymatic activity of normal controls. The p.Gly261ValfsTer20 variant along with another missense variant was determined to be in linkage disequilibrium with a specific haplotype indicating that it is a founder variant in the Japanese population (Yang et al. 2000). Based on the evidence and potential impact of frameshift variants, the p.Gly261ValfsTer20 variant is classified as pathogenic for holocarboxylase synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410410	SCV000919515	pathogenic	Holocarboxylase synthetase deficiency	2017-09-21	criteria provided, single submitter	clinical testing	Variant summary: The HLCS c.782delG (p.Gly261ValfsX20) variant results in a premature termination codon, predicted to cause a truncated or absent HLCS protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/276850 control chromosomes at a frequency of 0.0000181, which does not exceed the estimated maximal expected allele frequency of a pathogenic HLCS variant (0.0027839). The variant of interest has been reported in multiple compound heterozygote individuals and has been indicated to be a common mutation observed in Japanese (Yang_2001). In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410410	SCV000953901	pathogenic	Holocarboxylase synthetase deficiency	2023-09-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly261Valfs*20) in the HLCS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HLCS are known to be pathogenic (PMID: 16134170). This variant is present in population databases (rs771944310, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 7842009, 9870216, 11735028). This variant is also known as delG1067, c.780delG. ClinVar contains an entry for this variant (Variation ID: 203777). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000410410	SCV004199832	pathogenic	Holocarboxylase synthetase deficiency	2024-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000410410	SCV000022141	pathogenic	Holocarboxylase synthetase deficiency	2000-01-01	no assertion criteria provided	literature only
Counsyl	RCV000410410	SCV000485741	pathogenic	Holocarboxylase synthetase deficiency	2016-07-22	no assertion criteria provided	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV000410410	SCV000853119	pathogenic	Holocarboxylase synthetase deficiency	2017-06-07	no assertion criteria provided	curation
Natera, Inc.	RCV000410410	SCV001461053	pathogenic	Holocarboxylase synthetase deficiency	2020-09-16	no assertion criteria provided	clinical testing