Submissions for variant NM_015702.3(MMADHC):c.742C>T (p.Arg248Cys)

gnomAD frequency: 0.00001  dbSNP: rs544727246

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756344	SCV000884124	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing	The p.Arg248Cys variant (rs544727246) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. The p.Arg248Cys variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.002 percent (identified on 5 out of 246,046 chromosomes). A similar adjacent variant, p.Tyr249Cys, was reported in a patient with homocystinuria, and shown that the variant protein was ineffective in restoring methylcobalamine synthesis in disease-model cell culture (Coelho, 2008). Based on a crystal structure of MMADHC, Arg248 and Tyr249 are located in a domain near the cobalamine chaperone, MMACHC, binding site (Yamada, 2015). The arginine at position 248 is highly conserved considering sixteen species up to fruit fly (Alamut v2.9.0) and computational analyses of the p.Arg248Cys variant on protein structure and function indicates a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Arg248Cys variant with certainty.
GeneDx	RCV000756344	SCV001985128	uncertain significance	not provided	2020-01-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV001835948	SCV002778837	uncertain significance	Methylmalonic aciduria and homocystinuria type cblD	2021-11-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001835948	SCV003461337	uncertain significance	Methylmalonic aciduria and homocystinuria type cblD	2022-05-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 248 of the MMADHC protein (p.Arg248Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MMADHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 618213). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Natera, Inc.	RCV001835948	SCV002083913	uncertain significance	Methylmalonic aciduria and homocystinuria type cblD	2019-10-28	no assertion criteria provided	clinical testing