NM_000303.3(PMM2):c.58C>T (p.Pro20Ser) AND PMM2-congenital disorder of glycosylation

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 8, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000850396.11

Allele description [Variation Report for NM_000303.3(PMM2):c.58C>T (p.Pro20Ser)]

NM_000303.3(PMM2):c.58C>T (p.Pro20Ser)

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.58C>T (p.Pro20Ser)

HGVS:

NC_000016.10:g.8797940C>T
NG_009209.1:g.5128C>T
NG_033146.1:g.4709G>A
NM_000303.3:c.58C>TMANE SELECT
NP_000294.1:p.Pro20Ser
NC_000016.9:g.8891797C>T
NM_000303.2:c.58C>T

Protein change:

P20S

Links:

dbSNP: rs949271895

NCBI 1000 Genomes Browser:

rs949271895

Molecular consequence:

NM_000303.3:c.58C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PMM2-congenital disorder of glycosylation
Synonyms:: CDG Ia; CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE Ia; CDG 1A; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008907; MedGen: C0349653; Orphanet: 79318; OMIM: 212065

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000992591	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - PGEN	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 3, 2019)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001558414	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 8, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15844218, 20638314, 28492532
SCV002089461	Natera, Inc.	no assertion criteria provided	Uncertain significance (Oct 13, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000992591

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - PGEN

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 3, 2019)

unknown

research

PubMed (1)
[See all records that cite this PMID]

SCV001558414

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 8, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002089461

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Oct 13, 2020)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

A new insight into PMM2 mutations in the French population.

Le Bizec C, Vuillaumier-Barrot S, Barnier A, Dupré T, Durand G, Seta N.

Hum Mutat. 2005 May;25(5):504-5.

PubMed [citation]

PMID:: 15844218

See all PubMed Citations (4)

Details of each submission

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - PGEN, SCV000992591.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001558414.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces proline with serine at codon 20 of the PMM2 protein (p.Pro20Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with PMM2-congenital disorder of glycosylation (CDG-Ia) (PMID: 15844218, 20638314). ClinVar contains an entry for this variant (Variation ID: 689645). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Natera, Inc., SCV002089461.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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