ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs146448211
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Total submissions: 7
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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 pathogenic Holocarboxylase synthetase deficiency 2022-07-08 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. In at least one experimental study, a truncation downstream of this position was found to impair biotinylating activity, suggesting the C-terminal end of the protein is important for its functional activity (e.g. Campeau_2001). 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 is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as likely pathogenic (n=3) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000665201 SCV001200463 pathogenic Holocarboxylase synthetase deficiency 2024-02-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg665*) in the HLCS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acid(s) of the HLCS protein. This variant is present in population databases (rs146448211, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with holocarboxylase synthetase deficiency (PMID: 16134170, 27114915, 33123633). 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. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000665201 SCV002016599 likely pathogenic Holocarboxylase synthetase deficiency 2021-01-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000665201 SCV002795728 likely pathogenic Holocarboxylase synthetase deficiency 2024-01-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV000665201 SCV004199821 pathogenic Holocarboxylase synthetase deficiency 2024-03-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000665201 SCV002083717 likely pathogenic Holocarboxylase synthetase deficiency 2020-12-30 no assertion criteria provided clinical testing

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