Submissions for variant NM_015506.3(MMACHC):c.82-1G>A

dbSNP: rs1255179780

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672739	SCV000797875	likely pathogenic	Cobalamin C disease	2018-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672739	SCV000917673	likely pathogenic	Cobalamin C disease	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.82-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. Two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249094 control chromosomes (gnomAD). c.82-1G>A has been reported in the literature in homozygote and compound heterozygote individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria) (examples: Huemer_2014, Lerner-Ellis_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672739	SCV000941013	pathogenic	Cobalamin C disease	2023-09-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 556698). Disruption of this splice site has been observed in individuals with MMACHC-related conditions (PMID: 19370762, 25398587). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 of the MMACHC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595).
Genome-Nilou Lab	RCV000672739	SCV004172340	likely pathogenic	Cobalamin C disease	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000672739	SCV004193211	pathogenic	Cobalamin C disease	2024-02-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000672739	SCV005652262	likely pathogenic	Cobalamin C disease	2023-12-29	criteria provided, single submitter	clinical testing