ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.88C>G (p.Pro30Ala)

gnomAD frequency: 0.00001  dbSNP: rs202069145
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000381823 SCV000347921 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2018-01-13 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics RCV002519380 SCV003713179 uncertain significance Inborn genetic diseases 2022-10-27 criteria provided, single submitter clinical testing The c.88C>G (p.P30A) alteration is located in exon 1 (coding exon 1) of the HMGCS2 gene. This alteration results from a C to G substitution at nucleotide position 88, causing the proline (P) at amino acid position 30 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000381823 SCV004276035 uncertain significance 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2023-02-23 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 30 of the HMGCS2 protein (p.Pro30Ala). This variant is present in population databases (rs202069145, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with HMGCS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 292345). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breakthrough Genomics, Breakthrough Genomics RCV004691135 SCV005186859 uncertain significance not provided criteria provided, single submitter not provided

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