NM_000303.3(PMM2):c.422G>A (p.Arg141His) AND not provided

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Dec 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000078590.46

Allele description [Variation Report for NM_000303.3(PMM2):c.422G>A (p.Arg141His)]

NM_000303.3(PMM2):c.422G>A (p.Arg141His)

Gene:

PMM2:phosphomannomutase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.2

Genomic location:

Preferred name:

NM_000303.3(PMM2):c.422G>A (p.Arg141His)

HGVS:

NC_000016.10:g.8811153G>A
NG_009209.1:g.18341G>A
NM_000303.3:c.422G>AMANE SELECT
NP_000294.1:p.Arg141His
NP_000294.1:p.Arg141His
NC_000016.9:g.8905010G>A
NM_000303.2:c.422G>A
O15305:p.Arg141His

Protein change:

R141H; ARG141HIS

Links:

UniProtKB: O15305#VAR_006105; OMIM: 601785.0001; dbSNP: rs28936415

NCBI 1000 Genomes Browser:

rs28936415

Molecular consequence:

NM_000303.3:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Ppp1r36dn Ppp1r36 downstream neighbor [Mus musculus]
Ppp1r36dn Ppp1r36 downstream neighbor [Mus musculus]
Gene ID:100041694

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000230903	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Nov 11, 2015)	germline	clinical testing	Citation Link,
SCV000321929	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 11, 2019)	germline	clinical testing	Citation Link,
SCV000511512	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 6, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001247655	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2023)	germline	clinical testing	Citation Link,
SCV001554206	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV001712854	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 31, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9497260, 11517108, 21541725, 25355454, 19357119, 26014514, 9140401, 10602363, 20301289, 25741868
SCV001800330	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001925184	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001957730	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	18	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	46	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A.

Matthijs G, Schollen E, Van Schaftingen E, Cassiman JJ, Jaeken J.

Am J Hum Genet. 1998 Mar;62(3):542-50.

PubMed [citation]

PMID:: 9497260
PMCID:: PMC1376957

Congenital disorder of glycosylation type Ia (CDG-Ia): phenotypic spectrum of the R141H/F119L genotype.

Kjaergaard S, Schwartz M, Skovby F.

Arch Dis Child. 2001 Sep;85(3):236-9.

PubMed [citation]

PMID:: 11517108
PMCID:: PMC1718926

See all PubMed Citations (10)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000230903.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	46	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		46	not provided	not provided	not provided

From GeneDx, SCV000321929.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

One of the most common pathogenic PMM2 variants reported among European individuals with CDG-1a (Kjaergaard et al., 2001), but has only been identified in the compound heterozygous state and is predicted to be homozygous lethal (Freeze and Westpahl, 2001); Published functional studies demonstrate a damaging effect with reduced enzyme stability and catalytic activity below detection limits (Vega et al., 2011); This variant is associated with the following publications: (PMID: 25192236, 20981092, 31902100, 28373276, 28940310, 22975760, 10700701, 25333069, 21228398, 11530212, 9140401, 19357119, 11517108, 11589167, 21541725, 27053713, 28139241, 26488408, 23988505, 25108116, 26014514, 16376131, 18629883, 19165618, 28425223, 28566178, 28820871, 30609409, 30487145, 30991241, 31474318, 31391289, 31628766, 31981409, 31980526, 32595772, 32581362, 32064623, 31589614, 33163565, 32874916, 31736265, 33643843, 33204593, 33413482)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000511512.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.004257	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001247655.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	18	not provided	not provided	clinical testing	not provided

Description

PMM2: PM3:Very Strong, PM2, PS3:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		18	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001554206.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The PMM2 p.R141H is one of the most frequent pathogenic variants found to cause congenital disorder of glycosylation type 1a (CDG1a) and is reported in ~40% of European CDG1a cases. This variant has only been found in the compound heterozygous state, suggesting that homozygosity for the p.A141H variant would be lethal (Matthijs_1998_PMID:9497260; Kjaergaard_1998_PMID:9781039). The variant was identified in dbSNP (ID: rs28936415) and ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, Laboratory for Molecular Medicine, Genetic Services Laboratory, University of Chicago and 15 other laboratories). The variant was identified in control databases in 891 of 224376 chromosomes at a frequency of 0.003971 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 177 of 21196 chromosomes (freq: 0.008351), Ashkenazi Jewish in 71 of 9376 chromosomes (freq: 0.007573), European (non-Finnish) in 511 of 94084 chromosomes (freq: 0.005431), Other in 27 of 6220 chromosomes (freq: 0.004341), Latino in 64 of 30676 chromosomes (freq: 0.002086), South Asian in 24 of 25492 chromosomes (freq: 0.000942), African in 15 of 20700 chromosomes (freq: 0.000725), and East Asian in 2 of 16632 chromosomes (freq: 0.00012). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.R141 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Functional studies have demonstrated loss of PMM2 protein activity from the p.R141H variant (Vega_2011_PMID:21541725; Yuste-Checa_2015_PMID:26014514). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001712854.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001800330.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001925184.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001957730.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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