ClinVar Miner

Submissions for variant NM_000411.8(HLCS):c.1993C>T (p.Arg665Ter) (rs146448211)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665201 SCV000789276 likely pathogenic Holocarboxylase synthetase deficiency 2017-01-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000665201 SCV000919516 likely pathogenic Holocarboxylase synthetase deficiency 2019-03-25 criteria provided, single submitter clinical testing Variant summary: HLCS c.1993C>T (p.Arg665X) results in a premature termination codon, predicted to cause a truncation of the encoded protein (leading to the removal of the biotin protein ligase, C-terminal domain, IPR003142) 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 (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HLCS causing Holocarboxylase Synthetase Deficiency (2E-05 vs 2.80E-03), allowing no conclusion about variant significance. This variant has been reported in the literature in individuals affected with Holocarboxylase Synthetase Deficiency (Suzuki 2005, Donti 2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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