ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.442A>G (p.Met148Val)

gnomAD frequency: 0.00001  dbSNP: rs764841449
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674632 SCV000800002 uncertain significance Holocarboxylase synthetase deficiency 2018-05-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003117481 SCV003800760 uncertain significance not specified 2023-01-20 criteria provided, single submitter clinical testing Variant summary: HLCS c.1A>G (p.Met1Val aka. p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two potential in-frame start codons (ATG) are located downstream in the same exon (at Met7), and in the next exon (Met58). In vitro functional studies suggest that the HLCS protein can be translated from all three (i.e. Met1, Met7 and Met58) translation initiation codons, and these isoforms occur in human tissues (PMIDs: 9630604, 20153287). No truncations upstream of the alternative initiation codons are reported in affected individuals (HGMD), in addition, in vitro experiments demonstrated that N-terminal truncations starting at Met58 (and even at Ala80) resulted in a fully active enzyme (PMID 11124959). The variant allele was found at a frequency of 1.2e-05 in 251460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1A>G in individuals affected with Holocarboxylase Synthetase Deficiency and no experimental evidence demonstrating its impact on protein function have 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.