Submissions for variant NM_015702.3(MMADHC):c.646C>G (p.Arg216Gly)

gnomAD frequency: 0.00181  dbSNP: rs141093638

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186037	SCV000239001	uncertain significance	not specified	2017-02-15	criteria provided, single submitter	clinical testing	The R216G variant in the MMADHC gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R216G variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R216G variant is a non-conservative amino acid substitution, which occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R216G as a variant of unknown significance. This variant has been observed to be maternally inherited.
Eurofins Ntd Llc (ga)	RCV000186037	SCV000708796	likely benign	not specified	2017-05-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641147	SCV000762769	likely benign	Methylmalonic aciduria and homocystinuria type cblD	2024-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091563	SCV001247688	likely benign	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001128816	SCV001288309	likely benign	Disorders of Intracellular Cobalamin Metabolism	2018-01-12	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.
Illumina Laboratory Services, Illumina	RCV000641147	SCV001291096	uncertain significance	Methylmalonic aciduria and homocystinuria type cblD	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Natera, Inc.	RCV000641147	SCV001461405	benign	Methylmalonic aciduria and homocystinuria type cblD	2019-11-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927725	SCV004746171	likely benign	MMADHC-related disorder	2024-03-11	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).