Submissions for variant NM_015506.3(MMACHC):c.811A>G (p.Ser271Gly)

gnomAD frequency: 0.04960  dbSNP: rs35219601

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000245390	SCV000312561	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000287880	SCV000357933	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000245390	SCV001448403	benign	not specified	2020-11-27	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.811A>G (p.Ser271Gly) results in a non-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 0.015 in 280360 control chromosomes, predominantly at a frequency of 0.16 within the African or African-American subpopulation in the gnomAD database, including 323 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 53 fold of the estimated maximal expected allele frequency for a pathogenic variant in MMACHC causing Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001518858	SCV001727632	benign	Cobalamin C disease	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001541052	SCV001759003	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001518858	SCV004178237	likely benign	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001541052	SCV005260352	likely benign	not provided		criteria provided, single submitter	not provided
Clinical Genetics, Academic Medical Center	RCV000245390	SCV002034710	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000245390	SCV002035501	benign	not specified		no assertion criteria provided	clinical testing