Submissions for variant NM_015506.3(MMACHC):c.547_548del (p.Val183fs)

dbSNP: rs1305170860

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790832	SCV000331393	pathogenic	not provided	2013-05-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000266579	SCV000919667	pathogenic	Cobalamin C disease	2018-04-11	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.547_548delGT (p.Val183ThrfsX5) 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 (e.g. c.609G>A (p.Trp203X), c.615C>G (p.Tyr205X), c.666C>A (p.Tyr222X)). The variant was absent in 120978 control chromosomes. c.547_548delGT has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria), both as a homozygous and compound heterozygous allele (Lerner-Ellis 2006, Weisfeld-Adams 2013, Lerner-Ellis 2009). These data indicate that the variant is very likely to be associated with disease. One of these studies also reported that patients fibroblasts had decreased cobalamin coenzyme synthesis and decreased signal incorporation from radiolabeled propionate and 5-methyltetrahydrofolate (Lerner-Ellis 2006). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000266579	SCV000956601	pathogenic	Cobalamin C disease	2023-09-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MMACHC protein in which other variant(s) (p.Trp203*) have been determined to be pathogenic (PMID: 16311595, 23954310, 25772322). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 95704). This premature translational stop signal has been observed in individuals with methylmalonic aciduria and homocystinuria (PMID: 16311595, 19370762, 23954310). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Val183Thrfs*5) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 100 amino acid(s) of the MMACHC protein.
Genome-Nilou Lab	RCV000266579	SCV004178192	pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000266579	SCV004193162	pathogenic	Cobalamin C disease	2023-10-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001273230	SCV001456022	pathogenic	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing