Submissions for variant NM_015506.3(MMACHC):c.507_519del (p.Glu170fs)

dbSNP: rs1553162923

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671954	SCV000797001	pathogenic	Cobalamin C disease	2018-01-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000671954	SCV000917672	likely pathogenic	Cobalamin C disease	2018-11-16	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.507_519del13 (p.Glu170CysfsX36) 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 (eg. p.Trp203X, p.Tyr205X). The variant was absent in 246244 control chromosomes. c.507_519del13 has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria; Lerner-Ellis_2009, Wang_2010). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671954	SCV001236547	pathogenic	Cobalamin C disease	2024-02-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu170Cysfs*36) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 113 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 combined methylmalonic acidemia and hyperhomocysteinemia (PMID: 20924684). ClinVar contains an entry for this variant (Variation ID: 556017). 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.Ile190Tyrfs*13, p.Trp203*, p.Tyr205*) have been determined to be pathogenic (PMID: 16311595, 20631720, 23954310, 27383490). 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.
Genome-Nilou Lab	RCV000671954	SCV004178190	likely pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000671954	SCV004193180	pathogenic	Cobalamin C disease	2024-01-11	criteria provided, single submitter	clinical testing