Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000667730 | SCV000792226 | pathogenic | Cobalamin C disease | 2017-06-13 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000667730 | SCV000941526 | pathogenic | Cobalamin C disease | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 27 of the MMACHC protein (p.Gln27Arg). This variant is present in population databases (rs546099787, gnomAD 0.02%). This missense change has been observed in individual(s) with methylmalonic aciduria and/or homocystinuria, cblC type (PMID: 20924684, 28327205). 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: 552467). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000667730 | SCV004029139 | pathogenic | Cobalamin C disease | 2023-07-26 | criteria provided, single submitter | clinical testing | Variant summary: MMACHC c.80A>G (p.Gln27Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Computational tools predict no significant impact on normal splicing. However, to our knowledge, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 249530 control chromosomes (gnomAD). c.80A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Methylmalonic Acidemia With Homocystinuria and it has been suggested that it is a founder variant in individuals of Chinese ancestry (e.g. Lerner-Ellis_2006, Liu_2010). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16311595, 20631720). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Genome- |
RCV000667730 | SCV004178127 | pathogenic | Cobalamin C disease | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000667730 | SCV004193167 | pathogenic | Cobalamin C disease | 2023-10-17 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV001272218 | SCV001453987 | pathogenic | Methylmalonic acidemia with homocystinuria cblC | 2020-09-16 | no assertion criteria provided | clinical testing |