Submissions for variant NM_015506.3(MMACHC):c.616C>T (p.Arg206Trp)

gnomAD frequency: 0.00001  dbSNP: rs538023671

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000490478	SCV000800803	likely pathogenic	Cobalamin C disease	2018-01-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490478	SCV001372575	pathogenic	Cobalamin C disease	2024-05-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 206 of the MMACHC protein (p.Arg206Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 20610126, 20631720, 26149271). 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: 203832). 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.Arg206 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30157807). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000490478	SCV004193163	pathogenic	Cobalamin C disease	2023-12-02	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000490478	SCV005045086	pathogenic	Cobalamin C disease	2024-04-05	criteria provided, single submitter	clinical testing	The MMACHC c.616C>T (p.Arg206Trp) variant has been reported in at least four individuals in the compound heterozygous state affected with methylmalonic aciduria and homocystinuria, cblC type (Frattini D et al., PMID: 20610126; Lerner-Ellis JP et al., PMID: 16311595; Liu MY et al., PMID: 20631720; Zhong Y et al., PMID: 26149271). Another variant in the same codon, c.617G>A (p.Arg206Gln), has been reported in affected individuals and is considered pathogenic (Hu S et al., PMID: 30157807, ClinVar Variation ID: 848845). This variant is only observed on 1/249,530 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to MMACHC function. This variant has been reported in the ClinVar database as a germline pathogenic variant by three groups, likely pathogenic by one group and a variant of uncertain significance by one group. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490478	SCV000267397	uncertain significance	Cobalamin C disease	2016-03-18	flagged submission	reference population
Natera, Inc.	RCV000490478	SCV002089550	pathogenic	Cobalamin C disease	2020-09-02	no assertion criteria provided	clinical testing