ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.175C>A (p.Leu59Met)

gnomAD frequency: 0.00010  dbSNP: rs181428774
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756247 SCV000883997 uncertain significance not provided 2017-09-16 criteria provided, single submitter clinical testing The p.Leu59Met variant (rs181428774) has been reported at similar frequencies in case and control populations for porokeratosis and stroke, suggesting that this variant is not associated with these disorders (Yamada 2017 and Zhang 2015). This variant is also listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.46% in the East Asian population (identified in 87 out of 18,864 chromosomes). The leucine at codon 59 is moderately conserved considering 11 species (Alamut software v2.9.0), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). While the p.Leu59Met variant appears to be an ethnic-specific polymorphism in the East Asian population, the available evidence is insufficient to classify the clinical significance of this variant with certainty.
Illumina Laboratory Services, Illumina RCV001099374 SCV001255825 likely benign 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV001099374 SCV001660645 likely benign 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2022-11-06 criteria provided, single submitter clinical testing

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