Submissions for variant NM_000303.3(PMM2):c.324del (p.Ile110fs)

dbSNP: rs1555449314

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599337	SCV000709891	pathogenic	not provided	2020-10-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9497260)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000670380	SCV001337828	pathogenic	PMM2-congenital disorder of glycosylation	2020-01-18	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.324delG (p.Ile110LeufsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251440 control chromosomes. c.324delG has been reported in the literature in at-least one individual affected with Congenital Disorder of Glycosylation Type 1a and has been subsequently cited by others (example Matthjis_1998, Carchon_1999, Schollen_2002). These data indicate that the variant is likely to 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 without evidence for independent evaluation. All laboratories classified the variant as pathogenic(n=1)/likely pathogenic(n=1) using overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670380	SCV002243023	pathogenic	PMM2-congenital disorder of glycosylation	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile110Leufs*18) in the PMM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of PMM2-congenital disorder of glycosylation (CDG-Ia) (PMID: 9497260). ClinVar contains an entry for this variant (Variation ID: 503676). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000670380	SCV000795225	likely pathogenic	PMM2-congenital disorder of glycosylation	2017-11-01	no assertion criteria provided	clinical testing