Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001362080 | SCV001558081 | uncertain significance | 3-hydroxy-3-methylglutaryl-CoA synthase deficiency | 2022-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 318 of the HMGCS2 protein (p.Asn318Ser). This variant is present in population databases (rs766507770, gnomAD 0.09%). 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: 1053702). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HMGCS2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |
| Prevention |
RCV003399165 | SCV004105426 | uncertain significance | HMGCS2-related disorder | 2023-06-20 | criteria provided, single submitter | clinical testing | The HMGCS2 c.953A>G variant is predicted to result in the amino acid substitution p.Asn318Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.088% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-120299959-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Ambry Genetics | RCV004036825 | SCV004884699 | uncertain significance | Inborn genetic diseases | 2023-11-13 | criteria provided, single submitter | clinical testing | The c.953A>G (p.N318S) alteration is located in exon 5 (coding exon 5) of the HMGCS2 gene. This alteration results from a A to G substitution at nucleotide position 953, causing the asparagine (N) at amino acid position 318 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |