ClinVar Miner

Submissions for variant NM_000411.8(HLCS):c.782del (p.Gly261fs) (rs771944310)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410410 SCV000485741 pathogenic Holocarboxylase synthetase deficiency 2016-07-22 criteria provided, single submitter clinical testing
GeneDx RCV000185969 SCV000238927 pathogenic not provided 2016-09-21 criteria provided, single submitter clinical testing The c.782delG deletion pathogenic variant in the HLCS gene have been reported previously in association with holocarboxylase synthetase (HLCS) deficiency (Suzuki et al., 2005). The c.782delG deletion causes a frameshift starting with codon Glycine 261, changes this amino acid to a Valine residue and creates a premature Stop codon at position 20 of the new reading frame, denoted p.Gly261ValfsX20. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Illumina Clinical Services Laboratory,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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000410410 SCV000953901 pathogenic Holocarboxylase synthetase deficiency 2018-09-28 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. This variant is present in population databases (rs771944310, ExAC 0.03%). This variant has been observed in individuals affected with holocarboxylase synthetase deficiency (PMID: 7842009, 9870216, 11735028). This variant is also known as delG1067, c.780delG in the literature. ClinVar contains an entry for this variant (Variation ID: 203777). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in HLCS are known to be pathogenic (PMID: 16134170). For these reasons, this variant has been classified as Pathogenic.
SingHealth Duke-NUS Institute of Precision Medicine RCV000410410 SCV000853119 pathogenic Holocarboxylase synthetase deficiency 2017-06-07 no assertion criteria provided curation

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