Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000009840 | SCV000347904 | uncertain significance | 3-hydroxy-3-methylglutaryl-CoA synthase deficiency | 2017-04-27 | criteria provided, single submitter | clinical testing | The HMGCS2 c.1270C>T (p.Arg424Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg424Ter variant has been reported in two studies in which it is found in a total of two individuals with 3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency including in one in a compound heterozygous state with a missense variant, and in one in a heterozygous state with no second variant identified (Bouchard et al. 2001; Ramos et al. 2013). The variant was also found in a heterozygous state in at least two unaffected family members. The p.Arg424Ter variant was not found among 84 ethnically diverse control alleles, but is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. The evidence for this variant is limited. However, based on the potential impact of stop-gained variants and the evidence from the literature, the p.Arg424Ter variant is classified a variant of unknown significance but suspicious for pathogenicity for 3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Prevention |
RCV003407311 | SCV004108520 | pathogenic | HMGCS2-related disorder | 2023-04-05 | criteria provided, single submitter | clinical testing | The HMGCS2 c.1270C>T variant is predicted to result in premature protein termination (p.Arg424*). This variant has been reported in individuals with mitochondrial HMG-CoA synthase deficiency (Patient 2, Bouchard et al. 2001. PubMed ID: 11228257; Table 2, Shafqat et al. 2010. PubMed ID: 20346956; Ramos et al. 2013. PubMed ID: 23751782). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-120295927-G-A). Nonsense variants in HMGCS2 are expected to be pathogenic. This variant is interpreted as pathogenic. |
| Labcorp Genetics |
RCV000009840 | SCV004291982 | pathogenic | 3-hydroxy-3-methylglutaryl-CoA synthase deficiency | 2023-09-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 9258). This premature translational stop signal has been observed in individual(s) with HMG-CoA synthase deficiency (PMID: 11228257, 23751782). This variant is present in population databases (rs137852637, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg424*) 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). |
| OMIM | RCV000009840 | SCV000030061 | pathogenic | 3-hydroxy-3-methylglutaryl-CoA synthase deficiency | 2001-03-01 | no assertion criteria provided | literature only |