Submissions for variant NM_015506.3(MMACHC):c.433A>T (p.Ile145Leu)

dbSNP: rs74365027

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000374944	SCV000357926	likely benign	Disorders of Intracellular Cobalamin Metabolism	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000874747	SCV001016969	likely benign	Cobalamin C disease	2025-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001565856	SCV001789286	likely benign	not provided	2020-06-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000874747	SCV004178172	likely benign	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987500	SCV004803844	likely benign	not specified	2024-01-18	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.433A>T (p.Ile145Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 248518 control chromosomes, predominantly at a frequency of 0.0084 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.66 fold of the estimated maximal expected allele frequency for a pathogenic variant in MMACHC causing Methylmalonic Acidemia With Homocystinuria phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.433A>T in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 297486). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV001277243	SCV001464150	likely benign	Methylmalonic acidemia with homocystinuria cblC	2020-04-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003967841	SCV004784116	likely benign	MMACHC-related disorder	2022-05-23	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).