Submissions for variant NM_000303.3(PMM2):c.640-15479C>T

gnomAD frequency: 0.00004  dbSNP: rs1258107584

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665521	SCV000789659	likely pathogenic	PMM2-congenital disorder of glycosylation	2017-02-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665521	SCV001574941	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the PMM2 gene. It does not directly change the encoded amino acid sequence of the PMM2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 41 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 17307006, 33643843). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550704). Studies have shown that this variant results in the activation of a cryptic splice site in intron 7 (PMID: 19235233). 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	RCV000665521	SCV002103446	likely pathogenic	PMM2-congenital disorder of glycosylation	2022-02-08	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.640-15479C>T is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5' donor site and one predict the variant strengthens a 5' donor site. Functional studies have shown the variant to result in the creation of a pseudoexon, an additional 123 bp between exon 7 and 8 (Schollen_2007, Vega_2008). The variant was absent in 31398 control chromosomes. c.640-15479C>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (Schollen_2007, Lipinski_2021). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000665521	SCV002809258	pathogenic	PMM2-congenital disorder of glycosylation	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000665521	SCV004204829	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-03-18	criteria provided, single submitter	clinical testing
GeneDx	RCV004702278	SCV005201474	likely pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on gene splicing causing an in-frame insertion of a pseudoexon (Schollen et al., 2007; Vega et al., 2009); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 19235233, 33643843, 17307006, 19823873, 18571450)
OMIM	RCV000665521	SCV000028368	pathogenic	PMM2-congenital disorder of glycosylation	2009-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000665521	SCV002092442	likely pathogenic	PMM2-congenital disorder of glycosylation	2020-02-11	no assertion criteria provided	clinical testing