Submissions for variant NM_022132.5(MCCC2):c.1072+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155781	SCV003844809	likely pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.1072+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 a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251170 control chromosomes. To our knowledge, no occurrence of c.1072+1G>A in individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003600449	SCV004511739	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2023-01-09	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with MCCC2-related conditions. This variant is present in population databases (rs781013376, gnomAD 0.002%). This sequence change affects a donor splice site in intron 11 of the MCCC2 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 MCCC2 are known to be pathogenic (PMID: 11181649, 22642865).