rs398123312

Positions:

• chr16-8801827-TA-GC

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 same amino acid change has been previously reported as Pathogenicin 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]

PMM2 (HGNC:):

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/exons	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	1/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 12, 2023	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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMM2 function (PMID: 10922383, 11715002). 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. ClinVar contains an entry for this variant (Variation ID: 92807). This variant is present in population databases (rs398123312, gnomAD 0.0008%). 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). -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2016	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

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2024	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2020

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2024

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;