rs759513930

Positions:

chr16-8801910-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000303.3(PMM2):c.178G>T(p.Val60Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000702 in 1,566,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 9.34

Variant links:

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]

PMM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a chain Phosphomannomutase 2 (size 244) in uniprot entity PMM2_HUMAN there are 79 pathogenic changes around while only 2 benign (98%) in NM_000303.3

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-8801910-G-T is Pathogenic according to our data. Variant chr16-8801910-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 530390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8801910-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3 linkuse as main transcript	c.178G>T	p.Val60Leu	missense_variant, splice_region_variant	2/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1 linkuse as main transcript	c.6G>T	p.Met2Ile	missense_variant, splice_region_variant	1/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 linkuse as main transcript	c.178G>T	p.Val60Leu	missense_variant, splice_region_variant	2/8	1	NM_000303.3	ENSP00000268261	P1	O15305-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000245

AC:

AN:

245166

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000636

AC:

AN:

1414380

Hom.:

Cov.:

AF XY:

0.00000425

AC XY:

AN XY:

706232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:5Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	May 30, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2023	Variant summary: PMM2 c.178G>T (p.Val60Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (example:Gonzalez-Dominguez_2021). The variant allele was found at a frequency of 2.4e-05 in 245166 control chromosomes (gnomAD). c.178G>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation and Developmental brain disorder (example: Gonzalez-Dominguez_2021 and Aldinger_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 60 of the PMM2 protein (p.Val60Leu). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs759513930, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical and biochemical features consistent with PMM2-CDG (Invitae). 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: 530390). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 34277356). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMM2 related disorder (ClinVar ID: VCV000530390 / PMID: 26633542). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

PMM2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2024

The PMM2 c.178G>T variant is predicted to result in the amino acid substitution p.Val60Leu. This variant has been reported in the compound heterozygous state with a second disease-causing PMM2 variant in multiple individuals with congenital disorder of glycosylation type 1a (PMM2-CDG) (González-Domínguez et al. 2021. PubMed ID: 34277356; De Graef et al. 2023. PubMed ID: 37224763; Hall et al. 2024. PubMed ID: 39216211; PreventionGenetics internal data). It has also been reported in the presumed compound heterozygous state (with p.Arg141His) in a cohort of individuals with cerebellar malformations (Table S9, Aldinger et al. 2019. PubMed ID: 31474318). RNA sequencing analysis performed using cultured patient fibroblasts confirmed that the c.178G>T variant disrupted splicing at the adjacent canonical splice donor site, leading to the activation of two intronic cryptic donor sites (González-Domínguez et al. 2021. PubMed ID: 34277356). The inclusion of intronic sequence in the resulting mRNA is expected to lead to a frameshift (p.Val60Cysfs*3) and premature protein termination. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in PMM2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2023

Transversion change at the evolutionarily conserved last nucleotide position of exon 2 in a gene for which loss-of-function is a known mechanism of disease. In silico predictors support a potential splicing effect with the adjacent exon out of frame and studies in patient cells support this variant results in abnormal splicing (Gonzlez-Domnguez CA et al., 2021); This variant is associated with the following publications: (PMID: 26633542, 34277356) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Benign

-0.087

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.20

MutationTaster

Benign

1.0

A;D;D;D;D

Vest4

0.85

ClinPred

0.27

GERP RS

5.7

RBP_binding_hub_radar

0.85

RBP_regulation_power_radar

2.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.51

Position offset: 28

DS_DL_spliceai

0.43

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over