NM_017739.4(POMGNT1):c.1895+1G>T AND Autosomal recessive limb-girdle muscular dystrophy type 2O

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 21, 2019
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:: RCV001005010.11

Allele description [Variation Report for NM_017739.4(POMGNT1):c.1895+1G>T]

NM_017739.4(POMGNT1):c.1895+1G>T

Genes:

POMGNT1:protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-) [Gene - OMIM - HGNC]
TSPAN1:tetraspanin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_017739.4(POMGNT1):c.1895+1G>T

HGVS:

NC_000001.11:g.46189457C>A
NG_009205.3:g.35849G>T
NM_001243766.2:c.1869+27G>T
NM_001290129.2:c.1829+1G>T
NM_001290130.2:c.1466+1G>T
NM_001410783.1:c.1895+1G>T
NM_017739.4:c.1895+1G>TMANE SELECT
LRG_701t1:c.1869+27G>T
LRG_701t2:c.1895+1G>T
LRG_701:g.35849G>T
NC_000001.10:g.46655129C>A
NM_001290129.1:c.1829+1G>T
NM_017739.3:c.1895+1G>T

Links:

dbSNP: rs386834024

NCBI 1000 Genomes Browser:

rs386834024

Molecular consequence:

NM_001243766.2:c.1869+27G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001290129.2:c.1829+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001290130.2:c.1466+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001410783.1:c.1895+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_017739.4:c.1895+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2O
Synonyms:: MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 3; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY, LIMB-GIRDLE, POMGNT1-RELATED; Limb-Girdle Muscular Dystrophy Type 3C; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013161; MedGen: C3150417; Orphanet: 206564; OMIM: 613157

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001164571	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2018)	germline	research	PubMed (3) [See all records that cite these PMIDs] 22554691, 22323514, 25741868
SCV001368122	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 21, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001164571

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 3, 2018)

germline

research

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

SCV001368122

Centre for Mendelian Genomics, University Medical Centre Ljubljana

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 21, 2019)

unknown

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Novel POMGNT1 point mutations and intragenic rearrangements associated with muscle-eye-brain disease.

Saredi S, Ardissone A, Ruggieri A, Mottarelli E, Farina L, Rinaldi R, Silvestri E, Gandioli C, D'Arrigo S, Salerno F, Morandi L, Grammatico P, Pantaleoni C, Moroni I, Mora M.

J Neurol Sci. 2012 Jul 15;318(1-2):45-50. doi: 10.1016/j.jns.2012.04.008. Epub 2012 May 2.

PubMed [citation]

PMID:: 22554691
PMCID:: PMC3405532

Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies.

Devisme L, Bouchet C, Gonzalès M, Alanio E, Bazin A, Bessières B, Bigi N, Blanchet P, Bonneau D, Bonnières M, Bucourt M, Carles D, Clarisse B, Delahaye S, Fallet-Bianco C, Figarella-Branger D, Gaillard D, Gasser B, Delezoide AL, Guimiot F, Joubert M, Laurent N, et al.

Brain. 2012 Feb;135(Pt 2):469-82. doi: 10.1093/brain/awr357. Epub 2012 Feb 9.

PubMed [citation]

PMID:: 22323514

See all PubMed Citations (3)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164571.1

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

Description

The homozygous c.1895+1G>T variant in POMGNT1 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.007982% (22/275604) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs386834024). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that the c.1895+1G>T variant may impact protein function with abnormal splicing and reduced translation (PMID: 22554691). However, these types of assays may not accurately represent biological function. This variant has been observed in the compound heterozygous state, with two variants not reported in ClinVar, in 2 individuals with LGMD as reported by the literature (PMID: 22554691, 22323514). The presence of this variant in combination with a reported pathogenic variant and in an individual with LGMD increases the likelihood that the c.1895+1G>T variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences reported in the literature in individuals with LGMD. ACMG/AMP Criteria applied: PM2, PVS1, PS3 (Richards 2015).

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001368122.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.

#	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

Last Updated: Nov 10, 2024

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