16-8801910-G-T

Variant names:

• chr16-8801910-G-T
• rs759513930
• NM_000303.3:c.178G>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_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. 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 9.34
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation type I

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• PMM2-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 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, 6 uncertain in NM_000303.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 89 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: -1.3872 (below the threshold of 3.09). Trascript score misZ: -1.8083 (below the threshold of 3.09). GenCC associations: The gene is linked to PMM2-congenital disorder of glycosylation, congenital disorder of glycosylation type I.
• PP3: Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 530390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMM2	NM_000303.3	c.178G>T	p.Val60Leu	missense_variant, splice_region_variant	Exon 2 of 8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.6G>T	p.Met2Ile	missense_variant, splice_region_variant	Exon 1 of 6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.178G>T	p.Val60Leu	missense_variant, splice_region_variant	Exon 2 of 8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000245 AC: 6 AN: 245166 AF XY: 0.0000151

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000636 AC: 9 AN: 1414380 Hom.: 0 Cov.: 24 AF XY: 0.00000425 AC XY: 3 AN XY: 706232

African (AFR) AF: 0.00 AC: 0 AN: 32412

American (AMR) AF: 0.000202 AC: 9 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39082

South Asian (SAS) AF: 0.00 AC: 0 AN: 84954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070106

Other (OTH) AF: 0.00 AC: 0 AN: 58692

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:6 Uncertain:1

Feb 24, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (internal data). 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. -

Mar 13, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 23, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Sep 01, 2021

Genomic Diagnostics Laboratory, National Institute of Medical Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000303.3:c.178G>T is predicted to cause a miss sense variant p.Val60Leu, but functional analysis of this variant in an RNAm experiment (PMID: 34277356) has identified a Loss of function mechanism (PVS1). This variant was found in a proband with oligohydramnios, hypotonia, psychomotor retardation and esotropia who was also reported by our group (PMID: 32874916 ). This variant was identified in trans with a clearly pathogenic variant (PM3). This variant has a low frequency in our population (0.14 %) and in very low frequency in gnomAD (PM2 https://gnomad.broadinstitute.org/ version 2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied: PVS1, PM3, PM2. -

May 30, 2019

Genomic Medicine Lab, University of California San Francisco

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PMM2-related disorder Pathogenic:1

Sep 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Sep 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Benign	-0.087
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.20	D
PhyloP100		9.3
Vest4		0.85
ClinPred		0.27	T
GERP RS		5.7
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		2.6
Varity_R		0.54
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs759513930; hg19: chr16-8895767;