rs1339004837

Variant names:

• chr16-8804777-AT-A
• rs1339004837
• NM_000303.3:c.190delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000303.3(PMM2):​c.190delT​(p.Tyr64ThrfsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,460,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y64Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMM2 NM_000303.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.60
• Publications: 1 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-8804777-AT-A is Pathogenic according to our data. Variant chr16-8804777-AT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 554804.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.190delT	p.Tyr64ThrfsTer11	frameshift_variant	Exon 3 of 8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.7-1538delT		intron_variant	Intron 1 of 5		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.190delT	p.Tyr64ThrfsTer11	frameshift_variant	Exon 3 of 8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251372 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000137 AC: 2 AN: 1460342 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726566

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110650

Other (OTH) AF: 0.0000166 AC: 1 AN: 60328

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:5

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr64Thrfs*11) in the PMM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with congenital disorders of glycosylation (PMID: 28139241). ClinVar contains an entry for this variant (Variation ID: 554804). 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. -

Feb 10, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr64ThrfsX11 variant in PMM2 has been reported in 1 individual with congenital disorder of glycosylation, with no additional information about whether any other variants were identified (Perez-Cerda 2017 PMID: 28139241). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 554804) and was absent from large population studies (gnomAD v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 64 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the PMM2 gene is an established disease mechanism in autosomal recessive PMM2-congential disorder of glycosylation. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive PMM2-congential disorder of glycosylation. ACMG/AMP Criteria applied: PVS1, PM2_Supporting. -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

PMM2-related disorder Pathogenic:1

Sep 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMM2 c.190delT variant is predicted to result in a frameshift and premature protein termination (p.Tyr64Thrfs*11). This variant was reported in an individual with congenital disorder of glycosylation 1a (Pérez-Cerdá et al. 2017. PubMed ID: 28139241). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-8898634-AT-A). Frameshift variants in PMM2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -10

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

Other links and lift over

dbSNP: rs1339004837; hg19: chr16-8898634;