Submissions for variant NM_000303.3(PMM2):c.124G>A (p.Gly42Arg)

gnomAD frequency: 0.00001  dbSNP: rs755402538

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671748	SCV000796764	uncertain significance	PMM2-congenital disorder of glycosylation	2017-12-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671748	SCV001230003	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 42 of the PMM2 protein (p.Gly42Arg). This variant is present in population databases (rs755402538, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 12357336, 15844218). ClinVar contains an entry for this variant (Variation ID: 555844). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. 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.
GeneDx	RCV001756139	SCV001985340	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Reported heterozygous in an individual with CDG-1A and intermediated phosphomannomutase activity (Le Bizec et al., 2005); Reported in a patient with CDG-1a who also harbored a second missense variant (Schollen et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 15844218, 34426522, 16009061, 32457805, 35281664, 12357336)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824863	SCV002074458	uncertain significance	not specified	2022-01-28	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.124G>A (p.Gly42Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249876 control chromosomes (gnomAD). c.124G>A has been reported in the literature in compound heterozygous individuals affected with Congenital Disorder Of Glycosylation Type 1a (e.g. Schollen_2002, Tiwary_2022). In addition, Le Bizec et al (2005) describe a heterozygote individual with the variant exhibiting intermediate PMM activity. These data indicate that the variant may be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000671748	SCV002815739	uncertain significance	PMM2-congenital disorder of glycosylation	2022-02-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000671748	SCV004205252	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-03-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000671748	SCV001457165	uncertain significance	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing