Submissions for variant NM_015506.3(MMACHC):c.565del (p.Arg189fs)

dbSNP: rs1257204721

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668639	SCV000793273	likely pathogenic	Cobalamin C disease	2017-08-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668639	SCV001360886	pathogenic	Cobalamin C disease	2022-02-07	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.565delC (p.Arg189ValfsX21) 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 249562 control chromosomes (gnomAD). c.565delC has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) (examples: Lerner-Ellis_2009, Fischer_2014 and Ricci_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000668639	SCV002233607	pathogenic	Cobalamin C disease	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg189Valfs*21) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the MMACHC protein. This variant is present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria and homocystinuria (PMID: 16311595, 19370762, 24599607, 31503356). ClinVar contains an entry for this variant (Variation ID: 553238). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000668639	SCV004178197	likely pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000668639	SCV004193196	pathogenic	Cobalamin C disease	2023-05-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000668639	SCV002089545	pathogenic	Cobalamin C disease	2020-04-04	no assertion criteria provided	clinical testing