Submissions for variant NM_015506.3(MMACHC):c.567dup (p.Ile190fs)

gnomAD frequency: 0.00001  dbSNP: rs1463495909

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672749	SCV000797885	pathogenic	Cobalamin C disease	2018-02-14	criteria provided, single submitter	clinical testing
Invitae	RCV000672749	SCV000955269	pathogenic	Cobalamin C disease	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile190Tyrfs*13) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 93 amino acid(s) of the MMACHC protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of combined methylmalonic aciduria and homocystinuria (PMID: 21835369, 26149271, 27383490). 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: 556708). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the MMACHC protein in which other variant(s) (p.Trp203*) have been determined to be pathogenic (PMID: 16311595, 20631720, 23954310, 27383490, 28327205). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000672749	SCV001162916	pathogenic	Cobalamin C disease		criteria provided, single submitter	clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV000672749	SCV001739474	pathogenic	Cobalamin C disease	2020-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000672749	SCV002815260	pathogenic	Cobalamin C disease	2021-07-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672749	SCV003801111	pathogenic	Cobalamin C disease	2023-01-08	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.567dupT (p.Ile190TyrfsX13) 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. The variant allele was found at a frequency of 1.2e-05 in 249560 control chromosomes. c.567dupT has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) (example, Ji_2019, Liu_2010). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000672749	SCV004178199	pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001273233	SCV001456025	pathogenic	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing