ClinVar Miner

Submissions for variant NM_000411.8(HLCS):c.1533dup (p.Val512fs) (rs767533946)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411747 SCV000486266 likely pathogenic Holocarboxylase synthetase deficiency 2016-07-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411747 SCV000915951 uncertain significance Holocarboxylase synthetase deficiency 2018-12-13 criteria provided, single submitter clinical testing The HLCS c.1533dupT (p.Val512CysfsTer65) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Val512CysfsTer65 variant has been reported in two studies, in which it is found in two individuals with holocarboxylase synthetase deficiency, including in a compound heterozygous state in one individual and in a heterozygous state in a second individual who also carries two additional missense variants of unknown phase (DaRe et al. 2013; Reid et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000095 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of frameshift variants and evidence from the literature, the p.Val512CysfsTer65 variant is classified as a variant of unknown significance but suspicious for holocarboxylase synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000411747 SCV000956502 pathogenic Holocarboxylase synthetase deficiency 2018-11-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val512Cysfs*65) in the HLCS gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs767533946, ExAC 0.001%). This variant has been observed in an individual affected with a mitochondrial disorder (PMID: 24215330). ClinVar contains an entry for this variant (Variation ID: 370850). Loss-of-function variants in HLCS are known to be pathogenic (PMID: 16134170). For these reasons, this variant has been classified as Pathogenic.

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