ClinVar Genomic variation as it relates to human health

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32481360, 32071835, 25398587, 30178268, 30197982, 19370762, 24210589)

Variant summary: MMACHC c.389A>G (p.Tyr130Cys) results in a non-conservative amino acid change in 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 0.00012 in 249408 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in MMACHC causing Methylmalonic Acidemia with Homocystinuria (0.0032), allowing no conclusion about variant significance. The variant, c.389A>G, has been reported in the literature in several compound heterozygous individuals affected with Methylmalonic Acidemia with Homocystinuria (e.g. Lerner-Ellis_2009, Cornec-LeGall_2014, Higashimoto_2020, Bourque_2021), including a family with three affected individuals (Higashimoto_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=1), likely pathogenic (n=4) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

The MMACHC c.389A>G variant is predicted to result in the amino acid substitution p.Tyr130Cys. This variant has previously been reported, in the heterozygous state with a second pathogenic MMACHC variant, in patients with both early and late-onset methylmalonic aciduria and homocystinuria, cblC type (Lerner-Ellis et al. 2009. PubMed ID: 19370762; Cornec-Le Gall et al. 2014. PubMed ID: 24210589; Lemoine et al. 2018. PubMed ID: 30197982; Higashimoto et al. 2020. PubMed ID: 32071835; Bourque et al. 2021. PubMed ID: 33473346). We have also observed this variant at PreventionGenetics in the heterozygous state, along with a second pathogenic variant, in one affected patient. A different amino acid change affecting the same amino acid has also been reported in cblC patients (e.g., Lerner-Ellis et al. 2006. PubMed ID: 16311595). Based on the collective evidence, we classify this variant as pathogenic.

PP3, PM2, PM3_strong

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 130 of the MMACHC protein (p.Tyr130Cys). This variant is present in population databases (rs200094982, gnomAD 0.02%). This missense change has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 19370762, 24210589; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 297484). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. This variant disrupts the p.Tyr130 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been observed in individuals with MMACHC-related conditions (PMID: 16311595, 19370762), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with methylmalonic aciduria and homocystinuria, cblC type (MIM#277400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (33 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated methylmalonic aciduria and homocystinuria type C family domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Tyr130His)) has been reported several times as likely pathogenic or pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as a VUS, but many times as likely pathogenic or pathogenic, and has been observed in multiple compound heterozygous individuals with cobalamin C deficiency (ClinVar, PMID: 30197982). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign