Submissions for variant NM_000303.3(PMM2):c.442G>A (p.Asp148Asn)

gnomAD frequency: 0.00014  dbSNP: rs148032587

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000514031	SCV000230902	pathogenic	not provided	2014-06-04	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514031	SCV000610832	pathogenic	not provided	2017-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624392	SCV000741807	pathogenic	Inborn genetic diseases	2016-09-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000178754	SCV000816991	pathogenic	PMM2-congenital disorder of glycosylation	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 148 of the PMM2 protein (p.Asp148Asn). This variant is present in population databases (rs148032587, gnomAD 0.03%). This missense change has been observed in individual(s) with PMM2-CDG (CDG-Ia) (PMID: 10801058, 11715002, 18203160). 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: 197659). 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%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 11715002). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000514031	SCV001820829	pathogenic	not provided	2022-02-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Westphal et al., 2001); 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: 26014514, 28425223, 18203160, 11715002, 25525159, 9140401, 10527672, 10602363, 10854097, 15844218, 21949237, 24498599, 26488408, 26805780, 28373276, 28492532, 11058895, 21811164, 11343337, 10801058, 32874916, 19176971, 31589614, 33413482, 32841164, 32635232)
Myriad Genetics, Inc.	RCV000178754	SCV002060233	likely pathogenic	PMM2-congenital disorder of glycosylation	2021-11-09	criteria provided, single submitter	clinical testing	NM_000303.2(PMM2):c.442G>A(D148N) is a missense variant classified as likely pathogenic in the context of congenital disorder of glycosylation type Ia. D148N has been observed in cases with relevant disease (PMID: 18203160, 11715002, 10801058, 33413482, 32635232). Functional assessments of this variant are available in the literature (PMID: 11715002). D148N has been observed in population frequency databases (gnomAD: NFE 0.04%). In summary, NM_000303.2(PMM2):c.442G>A(D148N) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Genetic Services Laboratory, University of Chicago	RCV000514031	SCV002064517	likely pathogenic	not provided	2018-05-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000178754	SCV002570574	pathogenic	PMM2-congenital disorder of glycosylation	2022-07-28	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.442G>A (p.Asp148Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 176372 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (0.00016 vs 0.0056), allowing no conclusion about variant significance. c.442G>A has been reported in the literature in compound heterozygous individuals affected with Congenital Disorder Of Glycosylation Type 1a (Imtiaz_2000, Matthijs_2000, Westphal_2001, Franscisco_2020). These data indicate that the variant is likely to be associated with disease. At least one functional study reports the variant results in reducing enzyme activity (Westphal_2001). Eight Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=6) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003416095	SCV004116447	pathogenic	PMM2-related disorder	2022-12-01	criteria provided, single submitter	clinical testing	The PMM2 c.442G>A variant is predicted to result in the amino acid substitution p.Asp148Asn. This variant has been reported in patients with congenital disorder of glycosylation 1a (see, for example, Imtiaz et al. 2000. PubMed ID: 10801058; Westphal et al. 2001. PubMed ID: 11715002; Starosta et al. 2021. PubMed ID: 33413482; Francisco et al. 2020. PubMed ID: 32635232). This variant was also described, along with a second potentially causative variant, in an individual with abnormal transferrin isoforms (Schon et al. 2021. PubMed ID: 34732400, supplementary data), and in vitro functional data suggest that this variant results in a thermolabile enzyme (Westphal et al. 2001. PubMed ID: 11715002). This variant was also described in the compound heterozygous state, along with a promoter variant, in a patient with polycystic kidney disease and hyperinsulinemic hypoglycemia, an allelic disorder to classic CDG type 1a (Moreno Macian et al. 2020. PubMed ID: 32841164). This variant is reported in 0.030% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-8905030-G-A). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000178754	SCV004204842	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-20	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000178754	SCV005398872	pathogenic	PMM2-congenital disorder of glycosylation	2024-10-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation type Ia (MIM# 212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The clinical manifestations and course are highly variable, ranging from infants who pass away in the first year of life to mildly affected adults (PMID: 20301289). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (873 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated PMM domain. (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Asp148Tyr) has a single likely pathogenic report in ClinVar and p.(Asp148Met) has been identified in an affected individual (PMID: 18203160). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has many pathogenic and likely pathogenic reports and has been identified in multiple affected individuals (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV000178754	SCV001457175	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000514031	SCV001553757	pathogenic	not provided		no assertion criteria provided	clinical testing	The PMM2 p.D148N variant was identified in 2 of 36 proband chromosomes (frequency: 0.056) from families with congenital disorders of glycosylation (CDG) type 1A (Imtiaz_2000_PMID:10801058; Westphal_2001_PMID:11715002). The variant was identified in dbSNP (ID: rs148032587), ClinVar (classified as likely pathogenic by Counsyl and as pathogenic by Invitae, Ambry Genetics, EGL Genetics and the Center for Pediatric Genomic Medicine at Children's Mercy Hospital and Clinics) and LOVD 3.0 (classified as pathogenic). The variant was also identified in control databases in 32 of 207784 chromosomes at a frequency of 0.000154 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 26 of 86006 chromosomes (freq: 0.000302), African in 4 of 19396 chromosomes (freq: 0.000206) and South Asian in 2 of 24218 chromosomes (freq: 0.000083), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish) or Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Although computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein, the p.D148 residue is highly conserved in mammals and other organisms. Further, expression of a vector carrying the p.D148N variant showed decreased PMM activity compared to wildtype (Westphal_2001_PMID:11715002). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.