NM_017739.4(POMGNT1):c.1284+2_1284+19del AND Muscular dystrophy-dystroglycanopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 24, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002523849.2

Allele description [Variation Report for NM_017739.4(POMGNT1):c.1284+2_1284+19del]

NM_017739.4(POMGNT1):c.1284+2_1284+19del

Genes:

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

Variant type:

Deletion

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_017739.4(POMGNT1):c.1284+2_1284+19del

HGVS:

NC_000001.11:g.46192513_46192530del
NG_009205.3:g.32790_32807del
NM_001243766.2:c.1284+2_1284+19del
NM_001290129.2:c.1218+2_1218+19del
NM_001290130.2:c.855+2_855+19del
NM_017739.4:c.1284+2_1284+19delMANE SELECT
LRG_701t1:c.1284+2_1284+19del
LRG_701t2:c.1284+2_1284+19del
LRG_701:g.32790_32807del
NC_000001.10:g.46658171_46658188del
NC_000001.10:g.46658185_46658202del
NG_009205.2:g.32790_32807del
NM_017739.3:c.1284+2_1284+19del18

Links:

dbSNP: rs1057516409

NCBI 1000 Genomes Browser:

rs1057516409

Molecular consequence:

NM_001243766.2:c.1284+2_1284+19del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001290129.2:c.1218+2_1218+19del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001290130.2:c.855+2_855+19del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_017739.4:c.1284+2_1284+19del - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Muscular dystrophy-dystroglycanopathy
Synonyms:: Congenital muscular dystrophy due to dystroglycanopathy
Identifiers:: MONDO: MONDO:0018276; MedGen: C5679911; Orphanet: 370953

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003761171	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 24, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003761171

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 24, 2023)

germline

curation

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	unknown	not provided	not provided	not provided	not provided	not provided	curation

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

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761171.1

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

Description

The c.1284+2_1284+19del variant in POMGNT1 has not been reported in the literature in individuals with muscular dystrophy-dystroglycanopathy, but has been identified in 0.002% (2/113694) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: dbSNP ID rs1057516409). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID #370335) and has been interpreted as likely pathogenic by Counsyl and Invitae. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. Loss of function of the POMGNT1 gene is an established disease mechanism in autosomal recessive POMGNT1-associated muscular dystrophy-dystroglycanopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).

#	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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