ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.2134C>T (p.Arg712Ter) (rs772791252)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489166 SCV000576938 pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing The R565X nonsense variant in the HLCS gene has been reported previously in association with holocarboxylase synthetase deciency in several unrelated individuals who were heterozygous for R565X and another variant in the HLCS gene (Sakamoto et al., 1998; Tang et al., 2003; Donti et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668883 SCV000919517 pathogenic Holocarboxylase synthetase deficiency 2018-08-03 criteria provided, single submitter clinical testing Variant summary: HLCS c.1693C>T (p.Arg565X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 246268 control chromosomes. c.1693C>T has been reported in the literature in individuals affected with Holocarboxylase Synthetase Deficiency (Sakamoto 1998, Tang 2003, Donti 2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Sakamoto_1998). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000668883 SCV001589928 pathogenic Holocarboxylase synthetase deficiency 2020-02-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg565*) in the HLCS gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs772791252, ExAC 0.006%). This variant has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 9870216). ClinVar contains an entry for this variant (Variation ID: 426486). Loss-of-function variants in HLCS are known to be pathogenic (PMID: 16134170). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000668883 SCV000793557 pathogenic Holocarboxylase synthetase deficiency 2017-08-18 no assertion criteria provided clinical testing

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