rs398123312

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1 PM1 PM2 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. 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 Lovd.

• Frequency: 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PS1: Transcript NM_000303.3 (PMM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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: 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 id 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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:3

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

- -

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. -

not provided Pathogenic:2

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) -

Dec 21, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123312; hg19: chr16-8895684;