rs148032587

chr16-8811173-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000303.3(PMM2):c.442G>A(p.Asp148Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,544,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D148Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.73

Genes affected

PMM2 (HGNC:9115): (phosphomannomutase 2) The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000303.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-8811173-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2740347.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 16-8811173-G-A is Pathogenic according to our data. Variant chr16-8811173-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8811173-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3	c.442G>A	p.Asp148Asn	missense_variant	5/8	ENST00000268261.9
PMM2	XM_047434215.1	c.193G>A	p.Asp65Asn	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.442G>A	p.Asp148Asn	missense_variant	5/8	1	NM_000303.3	P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152172 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000159 AC: 28 AN: 176372 Hom.: 0 AF XY: 0.000171 AC XY: 16 AN XY: 93724

Gnomad AFR exome AF: 0.0000936

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000826

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000613 AC: 853 AN: 1392144 Hom.: 0 Cov.: 28 AF XY: 0.000582 AC XY: 401 AN XY: 689580

Gnomad4 AFR exome AF: 0.000126

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000373

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000782

Gnomad4 OTH exome AF: 0.000225

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152172 Hom.: 0 Cov.: 34 AF XY: 0.000108 AC XY: 8 AN XY: 74336

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000297 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000583 AC: 5

ExAC AF: 0.000124 AC: 14

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 28, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 09, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 13, 2023	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 05, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2016

- -

PMM2-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.6	D;D
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.048	D;D
Polyphen		1.0	.;D
Vest4		0.95
MVP		0.98
MPC		0.016
ClinPred		0.79	D
GERP RS		5.3
Varity_R		0.79
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148032587; hg19: chr16-8905030;