Submissions for variant NM_015506.3(MMACHC):c.277-4C>G

gnomAD frequency: 0.00045  dbSNP: rs199889403

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000358926	SCV000357920	uncertain significance	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, 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.
GeneDx	RCV000432843	SCV000531461	likely benign	not specified	2016-09-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000870611	SCV001012130	likely benign	Cobalamin C disease	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522132	SCV003549347	uncertain significance	Inborn genetic diseases	2021-09-22	criteria provided, single submitter	clinical testing	The c.277-4C>G intronic alteration consists of a C to G substitution 4 nucleotides before exon 3 of the MMACHC gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000432843	SCV004241632	uncertain significance	not specified	2023-12-22	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.277-4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00032 in 249502 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MMACHC causing Methylmalonic Acidemia With Homocystinuria (0.00032 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.277-4C>G in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as VUS (n=2) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001273216	SCV001456008	likely benign	Methylmalonic acidemia with homocystinuria cblC	2020-09-16	no assertion criteria provided	clinical testing