Submissions for variant NM_015506.3(MMACHC):c.445_446del (p.Cys149fs)

dbSNP: rs796051999

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186034	SCV000238998	pathogenic	not provided	2014-10-16	criteria provided, single submitter	clinical testing	The c.445_446delTG mutation in the MMACHC gene causes a frameshift starting with codon Cysteine 149, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 32 of the new reading frame, denoted p.Cys149HisfsX32. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been previously reported to our knowledge, its is predicted to be pathogenic. The variant is found in MMACHC panel(s).
Baylor Genetics	RCV001004153	SCV001162909	pathogenic	Cobalamin C disease	2023-12-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001004153	SCV001227019	pathogenic	Cobalamin C disease	2023-08-18	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.Cys149Hisfs*32) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 134 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs777210603, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with cobalamin C deficiency (PMID: 26464686, 30157807). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.440_441del. ClinVar contains an entry for this variant (Variation ID: 203834).
Revvity Omics, Revvity	RCV001004153	SCV003824090	pathogenic	Cobalamin C disease	2022-08-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001004153	SCV004178176	pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001004153	SCV005185037	pathogenic	Cobalamin C disease	2024-05-22	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.445_446delTG (p.Cys149HisfsX32) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 248772 control chromosomes. c.445_446delTG has been reported in the literature in multiple compound heterozygous individuals affected with Methylmalonic Acidemia With Homocystinuria (eg. Hu_2018, Wang_2015, Wang_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30157807, 26464686, 29374341). ClinVar contains an entry for this variant (Variation ID: 203834). Based on the evidence outlined above, the variant was classified as pathogenic.
Neurology Department, Peking University First Hospital	RCV001004153	SCV001423142	uncertain significance	Cobalamin C disease	2020-04-23	no assertion criteria provided	research
Natera, Inc.	RCV001273222	SCV001456014	pathogenic	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing