Submissions for variant NM_015506.3(MMACHC):c.500del (p.Pro167fs)

dbSNP: rs1553162918

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668801	SCV000793464	pathogenic	Cobalamin C disease	2017-08-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668801	SCV001360887	pathogenic	Cobalamin C disease	2019-10-14	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.500delC (p.Pro167GlnfsX3) 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 was absent in 249506 control chromosomes (gnomAD). c.500delC has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria)(Ahrens-Nicklas_2017, Lerner-Ellis_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668801	SCV002246432	pathogenic	Cobalamin C disease	2022-07-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Pro167Glnfs*3) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 116 amino acid(s) of the MMACHC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cobalamin C deficiency (PMID: 26658511). ClinVar contains an entry for this variant (Variation ID: 553370). 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.
Genome-Nilou Lab	RCV000668801	SCV004178189	pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000668801	SCV004193218	pathogenic	Cobalamin C disease	2021-12-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000668801	SCV002089543	pathogenic	Cobalamin C disease	2019-12-02	no assertion criteria provided	clinical testing