NM_000303.3:c.95_96delTAinsGC

Variant names:

• chr16-8801827-TA-GC
• rs398123312
• NM_000303.3:c.95_96delTAinsGC

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1_Very_Strong PM1 PM5 PP2 PP3 PP5_Very_Strong

The NM_000303.3(PMM2):​c.95_96delTAinsGC​(p.Leu32Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.00000805 in 2 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L32V) has been classified as Likely pathogenic.

• Frequency: GnomAD MNV: 𝑓 0.0000080 Genomes: not found (cov: 33)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.53
• Publications: 26 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 22 ACMG points.

• PS1: Transcript NM_000303.3 (PMM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000303.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-8801826-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1945008.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 16-8801827-TA-GC is Pathogenic according to our data. Variant chr16-8801827-TA-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 92807.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.95_96delTAinsGC	p.Leu32Arg	missense_variant		ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.-78_-77delTAinsGC		5_prime_UTR_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.95_96delTAinsGC	p.Leu32Arg	missense_variant		1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

GnomAD MNV AF: 0.00000805 AC: 2 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:3

Jun 26, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PMM2 c.95_96delinsGC (p.Leu32delinsArg) causes an in-frame deletion/insertion resulting in a missense change. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/106694, which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178 (0.0055902). The variant of interest has been observed in multiple affected individuals as a compound heterozygote via multiple publications. In addition, multiple functional studies show the variant to impede PMM2 wild type functions. Furthermore, multiple reputable databases/clinical laboratories cite the variant as "likely pathogenic/pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 32 of the PMM2 protein (p.Leu32Arg). This variant is present in population databases (rs398123312, gnomAD 0.0008%). This missense change has been observed in individuals with PMM2-related conditions (PMID: 17451957, 19235233, 23988505, 25355454). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92807). 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 disruptive. Experimental studies have shown that this missense change affects PMM2 function (PMID: 10922383, 11715002). For these reasons, this variant has been classified as Pathogenic. -

Oct 29, 2018

Counsyl

Significance: 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. -

not provided Pathogenic:2

Dec 21, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with significantly reduced phosphomannomutase 2 enzyme activity compared to wild-type (PMID: 10922383, 11715002, 21541725); Deletion and insertion event resulting in an in-frame substitution of one amino acid; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23430838, 26502900, 12357336, 19235233, 25355454, 21541725, 11156536, 11715002, 17451957, 15844218, 11058895, 23988505, 34788024, 31589614, 34436420, 37955240, 36099812, 34863624, 38308356, 38129426, 35154715, 32635232, 33643843, 33619652, 38599261, 10922383) -

Inborn genetic diseases Pathogenic:1

Dec 10, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.95_96delTAinsGC (p.L32R) alteration, located in coding exon 2 of the PMM2 gene, results from an in-frame deletion of TA and insertion of GC at nucleotide positions 95 to 96. This results in the substitution of the arginine residue for a leucine residue at codon 32. Based on data from the Genome Aggregation Database (gnomAD) database, the PMM2 c.95T>G alteration was observed in <0.01% (2/248518) of total alleles studied. This mutation was identified in numerous Italian individuals with milder presentations of PMM2-related congenital disorders of glycosylation; all individuals had reduced PMM activity in leukocytes or fibroblasts and a second PMM2 variant identified (Barone, 2015). In E. coli and S. cerevisiae, this mutation demonstrated reduced PMM activity of approximately 40-45% of wild type levels (Vuillaumier-Barrot, 2000; Westphal, 2001; Vega, 2011) The p.L32R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

PMM2-related disorder Pathogenic:1

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMM2 c.95_96delinsGC variant is predicted to result in an in-frame deletion and insertion. This variant was reported in individuals with congenital disorder of glycosylation 1a (Vuillaumier-Barrot et al. 2000. PubMed ID: 10922383; Vega et al. 2009. PubMed ID: 19235233; Vega et al. 2011. PubMed ID: 21541725; Barone et al. 2014. PubMed ID: 25355454). This variant is considered to contribute to a mild neurological phenotype and appears to be particularly prevalent in individuals of Italian ancestry (Westphal et al. 2001. PubMed ID: 11715002; Barone et al. 2014. PubMed ID: 25355454). Functional studies showed that the p.Leu32Arg variant results in reduced enzyme activities (Westphal et al. 2001. PubMed ID: 11715002). This multi-nucleotide variant may be documented as two separate variants in cis (on the same allele) in a large population database (https://gnomad.broadinstitute.org/variant/16-8895684-TA-GC?dataset=gnomad_r2_1). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=170/130	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs398123312; hg19: chr16-8895684;