ClinVar Miner

Submissions for variant NM_005518.4(HMGCS2):c.1394del (p.Asn465fs)

dbSNP: rs779321975
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Endocrinology, Metabolism and Genetics, Henan Children's Hospital, Children's Hospital Affiliated to Zhengzhou University RCV001794525 SCV002032072 pathogenic 3-hydroxy-3-methylglutaryl-CoA synthase deficiency criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001794525 SCV002230146 pathogenic 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2023-03-02 criteria provided, single submitter clinical testing This variant is present in population databases (rs779321975, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Asn465Thrfs*10) in the HMGCS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HMGCS2 are known to be pathogenic (PMID: 20346956, 23751782, 25511235). This premature translational stop signal has been observed in individual(s) with HMG-CoA synthase deficiency (PMID: 35308163). ClinVar contains an entry for this variant (Variation ID: 1327465). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital RCV001794525 SCV002098041 pathogenic 3-hydroxy-3-methylglutaryl-CoA synthase deficiency 2022-02-15 no assertion criteria provided clinical testing The novel homozygous frameshift deletion variant c.1394delA (p. N465Tfs*9) has an allele frequency-0.0008% in gnomAD (aggregated) database and 0.0016% in 1000g. In-silico bioinformatic software mutation taster predicts this variant as Disease causing. Phenotype observed showed persistent metabolic acidosis, sudden onset fever, noisy breathing, altered sensorium. There was a clinical suspicion of inherited metabolic disorder. GCMS studies iterated similar clinical suspicion. HMG-CoA synthase-2 deficiency is an autosomal recessive disorder. Based on the phenotypic observation, we classify this variant as pathogenic.

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