Submissions for variant NM_007289.4(MME):c.1497+1G>C

gnomAD frequency: 0.00002  dbSNP: rs1395068713

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497869	SCV000590568	likely pathogenic	not provided	2024-09-10	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497869	SCV002278488	likely pathogenic	not provided	2024-03-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 of the MME 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 MME are known to be pathogenic (PMID: 26991897). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MME-related conditions. ClinVar contains an entry for this variant (Variation ID: 432802). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492080	SCV004241576	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2T	2023-12-21	criteria provided, single submitter	clinical testing	Variant summary: MME c.1497+1G>C 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 250698 control chromosomes. To our knowledge, no occurrence of c.1497+1G>C in individuals affected with Charcot-Marie Disease Axonal Type 2T and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.