rs151319324

chr16-8847797-G-Achr16-8847797-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BP4_Strong

The NM_000303.3(PMM2):c.713G>A(p.Arg238His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,613,530 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:2 O:1
• Conservation: PhyloP100: 1.94

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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, 8 uncertain in NM_000303.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-8847797-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.029460818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3	c.713G>A	p.Arg238His	missense_variant	8/8	ENST00000268261.9
PMM2	XM_047434215.1	c.464G>A	p.Arg155His	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.713G>A	p.Arg238His	missense_variant	8/8	1	NM_000303.3	P1
	ENST00000567942.1	n.283C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000574 AC: 144 AN: 250978 Hom.: 0 AF XY: 0.000597 AC XY: 81 AN XY: 135690

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000704

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000401 AC: 586 AN: 1461332 Hom.: 2 Cov.: 30 AF XY: 0.000407 AC XY: 296 AN XY: 726996

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000326

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74346

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000736 Hom.: 0

Bravo AF: 0.000442

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000593 AC: 72

EpiCase AF: 0.00104

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:9 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:1 Uncertain:2 Benign:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Likely pathogenic and reported on 10-26-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Morava/Kozicz Lab, Department of Clinical Genomics, Mayo Clinic	Mar 18, 2022	Missense variants in nearby residues reported in the HGMD in individuals with PMM2-CD (Stenson et al, 2014) (PM1). Observed with pathogenic variant on the opposite allele (in trans) in this patient (PM3). Parents are heterozygotes. The mode of inheritance is in line with previous reports (AR). The majority of missense variants in this gene are considered pathogenic (Stenson et al 2014). In silico analysis, which includes protein predictors and evolutionary conservation supports a deleterious effect (PP3). Observed in 0.0549 % (155/282362 alleles) in large population cohorts (Lek et al, 2016). Phenotype of the patient is in line with previously described PMM2-CDG patients (PP4). Other clinical tests stronly support PMM2-CDG diagnosis and indicate the variant is pathogenic. According to the guidelines of ACMG we classify this variant as likely pathogenic (2 PM and 2 PP). -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -

not provided Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2023	Reported in the heterozygous state in a patient with macrocephaly, dysmorphic features, hypotonia, and developmental delay in the published literature; however, a second PMM2 variant was not identified (Strong et al., 2021); 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: 9497260, 25681648, 10066032, 34132027, 24077912, 27231023, 34652821) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 19, 2022

Variant summary: PMM2 c.713G>A (p.Arg238His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 250978 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (0.00057 vs 0.0056), allowing no conclusion about variant significance. c.713G>A has been reported in the literature in individuals affected with Charcot-Marie-Tooth or Oral-facial-digital syndrome. These reports do not provide unequivocal conclusions about association of the variant with Congenital Disorder Of Glycosylation Type 1a. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=2, VUS n=4, likely benign n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.
Eigen	Benign	0.046
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Uncertain	0.62	D
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N;D;N
Sift	Benign	0.47	T;T;D
Sift4G	Benign	0.60	T;T;T
Polyphen		0.93	.;P;.
Vest4		0.42
MVP		0.91
MPC		0.021
ClinPred		0.084	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.74

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: rs151319324; hg19: chr16-8941654; COSMIC: COSV51632043; COSMIC: COSV51632043;