NM_000303.3(PMM2):c.66+1G>T AND PMM2-congenital disorder of glycosylation

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Dec 25, 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:: RCV000780612.13

Allele description [Variation Report for NM_000303.3(PMM2):c.66+1G>T]

NM_000303.3(PMM2):c.66+1G>T

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.66+1G>T

HGVS:

NC_000016.10:g.8797949G>T
NG_009209.1:g.5137G>T
NG_033146.1:g.4700C>A
NG_133047.1:g.817G>T
NG_133048.1:g.122G>T
NM_000303.3:c.66+1G>TMANE SELECT
NC_000016.9:g.8891806G>T
NM_000303.2:c.66+1G>T

Links:

dbSNP: rs937726878

NCBI 1000 Genomes Browser:

rs937726878

Molecular consequence:

NM_000303.3:c.66+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000918028	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 17, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15844218, 25497157, 20638314, 19862844 Citation Link,
SCV000992590	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]
SCV001200999	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 25, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16199547, 19862844, 15844218, 20638314, 28492532
SCV002813930	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 18, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004205314	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 30, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype.

Monin ML, Mignot C, De Lonlay P, Héron B, Masurel A, Mathieu-Dramard M, Lenaerts C, Thauvin C, Gérard M, Roze E, Jacquette A, Charles P, de Baracé C, Drouin-Garraud V, Khau Van Kien P, Cormier-Daire V, Mayer M, Ogier H, Brice A, Seta N, Héron D.

Orphanet J Rare Dis. 2014 Dec 11;9:207. doi: 10.1186/s13023-014-0207-4.

PubMed [citation]

PMID:: 25497157
PMCID:: PMC4266234

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918028.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: PMM2 c.66+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.4e-05 in 219708 control chromosomes (gnomAD). c.66+1G>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (Le Bizec_2005, Leticee_2010, Monin_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - PGEN, SCV000992590.1

#	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, SCV001200999.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change affects a donor splice site in intron 1 of the PMM2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with PMM2-congenital disorder of glycosylation (CDG-Ia) (PMID: 15844218, 20638314). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 632948). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002813930.1

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

From Baylor Genetics, SCV004205314.1

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

Last Updated: Sep 29, 2024

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