ClinVar Genomic variation as it relates to human health

The patient is affected with Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) and harbors the compound heterozygous HMGCS2 mutations, c.1480C>T, p.Arg494* (SCV 001169710 assigned) inherited from his father and c.1502G>C, p.Arg501Pro from his mother.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with HMGCS2 related disorder (PMID: 33045405). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 31910233, 33045405). A different missense change at the same codon (p.Arg501Gln) has been reported to be associated with HMGCS2 related disorder (PMID: 30477625). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 501 of the HMGCS2 protein (p.Arg501Pro). This variant is present in population databases (rs372079931, gnomAD 0.01%). This missense change has been observed in individual(s) with HMG-CoA synthase deficiency (PMID: 33045405; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 452101). 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 expected to disrupt HMGCS2 protein function. Experimental studies have shown that this missense change affects HMGCS2 function (PMID: 31910233). This variant disrupts the p.Arg501 amino acid residue in HMGCS2. Other variant(s) that disrupt this residue have been observed in individuals with HMGCS2-related conditions (PMID: 30477625), which suggests that this may be a clinically significant amino acid residue.

Variant summary: HMGCS2 c.1502G>C (p.Arg501Pro) results in a non-conservative amino acid change located in the Hydroxymethylglutaryl-coenzyme A synthase, C-terminal domain (IPR013746) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251332 control chromosomes. c.1502G>C has been reported in the literature in compound heterozygous individuals affected with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (e.g. Rojnueangnit_2020, Williams_2024). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absent 3-hydroxy-3-methylglutaryl CoA synthase activity in vitro (Bagheri-Fam_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31910233, 33045405, 38469099). ClinVar contains an entry for this variant (Variation ID: 452101). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The R501P variant in the HMGCS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R501P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R501P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.