Submissions for variant NM_015506.3(MMACHC):c.217C>T (p.Arg73Ter)

gnomAD frequency: 0.00001  dbSNP: rs796051995

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186024	SCV000238986	pathogenic	not provided	2021-08-24	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32943488, 31589614, 29731766, 31998365, 32208535, 31697851, 30564975, 30863077, 19760748, 20631720, 19447654, 24599607, 30157807, 20924684, 27383490, 26253414, 26149271, 16311595, 27751223)
Counsyl	RCV000671572	SCV000796560	pathogenic	Cobalamin C disease	2017-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV000671572	SCV000959332	pathogenic	Cobalamin C disease	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg73*) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). This variant is present in population databases (rs796051995, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 20631720, 27751223; Invitae). 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: 203825). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000671572	SCV001362050	pathogenic	Cobalamin C disease	2019-12-19	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.217C>T (p.Arg73X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249534 control chromosomes (gnomAD). c.217C>T has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria)(Hu_2018). 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. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000671572	SCV002792232	pathogenic	Cobalamin C disease	2022-02-23	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000671572	SCV004178138	pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000671572	SCV004193171	pathogenic	Cobalamin C disease	2023-10-10	criteria provided, single submitter	clinical testing
Neurology Department, Peking University First Hospital	RCV000671572	SCV001423144	pathogenic	Cobalamin C disease	2020-04-23	no assertion criteria provided	research
Natera, Inc.	RCV001273214	SCV001456006	pathogenic	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing