VCV000370499.7 - ClinVar

NM_017739.4(POMGNT1):c.1027-2_1027-1del

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(4); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_017739.4(POMGNT1):c.1027-2_1027-1del

Variation ID: 370499 Accession: VCV000370499.7

Type and length

Deletion, 2 bp

Location

Cytogenetic: 1p34.1 1: 46193389-46193390 (GRCh38) [ NCBI UCSC ] 1: 46659061-46659062 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 6, 2017	Feb 28, 2024	Aug 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_017739.4:c.1027-2_1027-1del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001243766.2:c.1027-2_1027-1del		splice acceptor
NM_001290129.2:c.961-2_961-1del		splice acceptor
NM_001290130.2:c.598-2_598-1del		splice acceptor
NM_017739.3:c.1027-2_1027-1delAG
NC_000001.11:g.46193389_46193390del
NC_000001.10:g.46659061_46659062del
NG_009205.3:g.31916_31917del
LRG_701:g.31916_31917del
LRG_701t1:c.1027-2_1027-1del
LRG_701t2:c.1027-2_1027-1del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:46193388:CT:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA16040749 dbSNP: rs1057516536 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
POMGNT1		-	-	GRCh38 GRCh37	262	1428
TSPAN1		-	-	GRCh38 GRCh37	15	1157

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Muscle eye brain disease	Likely pathogenic (1)	criteria provided, single submitter	Feb 19, 2016	RCV000408976.2
Autosomal recessive limb-girdle muscular dystrophy type 2O Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 Retinitis pigmentosa 76	Likely pathogenic (1)	criteria provided, single submitter	Feb 20, 2022	RCV002505993.1
Muscular dystrophy-dystroglycanopathy	Uncertain significance (1)	criteria provided, single submitter	Jan 24, 2023	RCV002524621.2
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	Likely pathogenic (1)	criteria provided, single submitter	Aug 11, 2023	RCV003463792.1
Autosomal recessive limb-girdle muscular dystrophy type 2O Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	Likely pathogenic (1)	criteria provided, single submitter	May 1, 2023	RCV003766124.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 19, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000485840.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022
Likely pathogenic (Feb 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 Autosomal recessive limb-girdle muscular dystrophy type 2O Retinitis pigmentosa 76 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002810949.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jan 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Muscular dystrophy-dystroglycanopathy (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV003761176.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: The c.1027-2_1027-1del variant in POMGNT1 has not been reported in the literature in individuals with muscular dystrophy-dystroglycanopathy, but has been identified in 0.0009% (1/110894) of … (more) The c.1027-2_1027-1del variant in POMGNT1 has not been reported in the literature in individuals with muscular dystrophy-dystroglycanopathy, but has been identified in 0.0009% (1/110894) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: dbSNP ID rs1057516536). 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 #370499) and has been interpreted as likely pathogenic by Counsyl. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, the clinical significance of the c.1027-2_1027-1del variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting (Richards 2015). (less)
Likely pathogenic (Aug 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004205971.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Likely pathogenic (May 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2O Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004572873.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 16199547‚ 19299310‚ 20816175‚ 21447391‚ 26908613‚ 27391550 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 370499). This variant has not been reported in the literature in individuals affected with POMGNT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects a splice site in intron 11 of the POMGNT1 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 POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550). (less)

Comment:

The c.1027-2_1027-1del variant in POMGNT1 has not been reported in the literature in individuals with muscular dystrophy-dystroglycanopathy, but has been identified in 0.0009% (1/110894) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: dbSNP ID rs1057516536). 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 #370499) and has been interpreted as likely pathogenic by Counsyl. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, the clinical significance of the c.1027-2_1027-1del variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting (Richards 2015).

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 370499). This variant has not been reported in the literature in individuals affected with POMGNT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects a splice site in intron 11 of the POMGNT1 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 POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Homozygosity Mapping and Whole-Genome Sequencing Links a Missense Mutation in POMGNT1 to Autosomal Recessive Retinitis Pigmentosa.	Wang NH	Investigative ophthalmology & visual science	2016	PMID: 27391550
Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa.	Xu M	Human molecular genetics	2016	PMID: 26908613
Reactive gliosis of astrocytes and Müller glial cells in retina of POMGnT1-deficient mice.	Takahashi H	Molecular and cellular neurosciences	2011	PMID: 21447391
POMGnT1, POMT1, and POMT2 mutations in congenital muscular dystrophies.	Endo T	Methods in enzymology	2010	PMID: 20816175
Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study.	Mercuri E	Neurology	2009	PMID: 19299310
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs1057516536 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_017739.4(POMGNT1):c.1027-2_1027-1del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057516536 ...