ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.2434C>T (p.Arg812Ter) (rs146448211)

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Total submissions: 3
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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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000665201 SCV000919516 likely pathogenic Holocarboxylase synthetase deficiency 2021-06-26 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 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 2.8e-05 in 251488 control chromosomes (gnomAD). c.1993C>T has been reported in the literature in individuals affected with Holocarboxylase Synthetase Deficiency (e.g. Suzuki 2005, Donti 2016, Tangeraas_2020). 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. Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000665201 SCV001200463 likely pathogenic Holocarboxylase synthetase deficiency 2020-10-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HLCS gene (p.Arg665*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acids of the HLCS protein. This variant is present in population databases (rs146448211, ExAC 0.01%). This variant has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 16134170, 27114915). ClinVar contains an entry for this variant (Variation ID: 203770). This variant disrupts the C-terminus of the HLCS protein. Other variant(s) that disrupt this region (p.Arg665Aspfs*41) have been observed in individuals with HLCS-related conditions (PMID: 10190325). This suggests that this may be a clinically significant region of the protein. 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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