ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.2121+1G>A (rs1175936807)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664724 SCV000788730 likely pathogenic Holocarboxylase synthetase deficiency 2016-12-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000664724 SCV000915950 uncertain significance Holocarboxylase synthetase deficiency 2017-09-05 criteria provided, single submitter clinical testing The HLCS c.1680+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for holocarboxylase synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000664724 SCV001577558 likely pathogenic Holocarboxylase synthetase deficiency 2020-04-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the HLCS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with holocarboxylase synthetase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 550091). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HLCS are known to be pathogenic (PMID: 16134170). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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