ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.1974dup (p.Val659fs) (rs767533946)

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Total submissions: 5
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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 2020-07-28 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000411747 SCV000996254 pathogenic Holocarboxylase synthetase deficiency 2019-03-01 criteria provided, single submitter clinical testing This frameshifting variant in exon 9 of 12 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a heterozygous change in two patients with suspected metabolic disease (PMID 24215330, 27604308) and classified in the ClinVar database as Likely Pathogenic by a clinical laboratory (Variation ID: 370850). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (15/277210) and thus is presumed to be rare. Based on the available evidence, the c.1533dup, p.Val512CysfsTer65 variant is classified as Pathogenic.
GeneDx RCV001591046 SCV001822630 pathogenic not provided 2020-12-10 criteria provided, single submitter clinical testing Previously reported in a patient with a neurometabolic phenotype who was also found to have a second variant in the HLCS gene (Reid et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27604308, 24215330)

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