Submissions for variant NM_015506.3(MMACHC):c.800G>A (p.Arg267Gln)

gnomAD frequency: 0.00002  dbSNP: rs765822392

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703465	SCV000513639	uncertain significance	not provided	2021-04-19	criteria provided, single submitter	clinical testing	Also observed in an individual with cblC deficiency who also harbored c.271dupA but it is not known whether these variants occurred on the same (in cis) or opposite (in trans) chromosomes (Gizicki et al., 2014); Described as a benign and possibly benign variant (Lerner-Ellis et al., 2009; Koutmos et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21697092, 24126030, 19370762, 16311595)
Invitae	RCV000670026	SCV001416974	uncertain significance	Cobalamin C disease	2021-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 267 of the MMACHC protein (p.Arg267Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs765822392, ExAC 0.02%). This missense change has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 19370762, 24126030). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 378150). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Myriad Genetics, Inc.	RCV000670026	SCV002060350	uncertain significance	Cobalamin C disease	2021-10-20	criteria provided, single submitter	clinical testing	NM_015506.2(MMACHC):c.800G>A(R267Q) is a missense variant classified as a variant of uncertain significance in the context of methylmalonic aciduria and homocystinuria, cblC type. R267Q has been observed in cases with relevant disease (PMID: 16311595, 24126030). Functional assessments of this variant are not available in the literature. R267Q has been observed in population frequency databases (gnomAD: SAS 0.02%). In summary, there is insufficient evidence to classify NM_015506.2(MMACHC):c.800G>A(R267Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Ambry Genetics	RCV002524774	SCV003702806	uncertain significance	Inborn genetic diseases	2022-09-12	criteria provided, single submitter	clinical testing	The c.800G>A (p.R267Q) alteration is located in exon 4 (coding exon 4) of the MMACHC gene. This alteration results from a G to A substitution at nucleotide position 800, causing the arginine (R) at amino acid position 267 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000670026	SCV003808856	uncertain significance	Cobalamin C disease	2021-07-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000670026	SCV004178235	uncertain significance	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987527	SCV004804463	uncertain significance	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.800G>A (p.Arg267Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 248864 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MMACHC causing Methylmalonic Acidemia With Homocystinuria (6.8e-05 vs 0.0032), allowing no conclusion about variant significance. c.800G>A has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria), however the majority of these reports identified the variant as part of a complex allele with c.271dupA (p.R91Kfs) (e.g., Lerner-Ellis_2006, Lerner-Ellis_2009, Koutmos_2011, Gizicki_2014, Stranneheim_2021, Kacpura_2022). These reports therefore do not provide unequivocal conclusions about association of the variant with Methylmalonic Acidemia With Homocystinuria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24126030, 35156754, 19370762, 16311595, 33726816, 21697092). ClinVar contains an entry for this variant (Variation ID: 378150). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001275225	SCV001460149	likely benign	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing