VCV000365275.18 - ClinVar

NM_001077365.2(POMT1):c.697_699del (p.Asn233del)

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.

(8)

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(2); Uncertain significance(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001077365.2(POMT1):c.697_699del (p.Asn233del)

Variation ID: 365275 Accession: VCV000365275.18

Type and length

Deletion, 3 bp

Location

Cytogenetic: 9q34.13 9: 131509994-131509996 (GRCh38) [ NCBI UCSC ] 9: 134385381-134385383 (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	Dec 6, 2016	Oct 13, 2024	Sep 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001077365.2:c.697_699del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001070833.1:p.Asn233del	inframe deletion
NM_001077366.2:c.535_537del	NP_001070834.1:p.Asn179del	inframe deletion
NM_001136113.2:c.697_699del	NP_001129585.1:p.Asn233del	inframe deletion
NM_001136114.2:c.346_348del	NP_001129586.1:p.Asn116del	inframe deletion
NM_001353193.2:c.697_699del	NP_001340122.2:p.Asn233del	inframe deletion
NM_001353194.2:c.535_537del	NP_001340123.1:p.Asn179del	inframe deletion
NM_001353195.2:c.346_348del	NP_001340124.1:p.Asn116del	inframe deletion
NM_001353196.2:c.607_609del	NP_001340125.1:p.Asn203del	inframe deletion
NM_001353197.2:c.535_537del	NP_001340126.2:p.Asn179del	inframe deletion
NM_001353198.2:c.535_537del	NP_001340127.2:p.Asn179del	inframe deletion
NM_001353199.2:c.346_348del	NP_001340128.2:p.Asn116del	inframe deletion
NM_001353200.2:c.241_243del	NP_001340129.1:p.Asn81del	inframe deletion
NM_001374689.1:c.535_537del	NP_001361618.1:p.Asn179del	inframe deletion
NM_001374690.1:c.697_699del	NP_001361619.1:p.Asn233del	inframe deletion
NM_001374691.1:c.346_348del	NP_001361620.1:p.Asn116del	inframe deletion
NM_001374692.1:c.346_348del	NP_001361621.1:p.Asn116del	inframe deletion
NM_001374693.1:c.535_537del	NP_001361622.1:p.Asn179del	inframe deletion
NM_001374695.1:c.241_243del	NP_001361624.1:p.Asn81del	inframe deletion
NM_007171.3:c.697_699del
NM_007171.3:c.697_699delAAT
NM_007171.4:c.697_699del	NP_009102.4:p.Asn233del	inframe deletion
NR_148391.2:n.731_733del		non-coding transcript variant
NR_148392.2:n.883_885del		non-coding transcript variant
NR_148393.2:n.731_733del		non-coding transcript variant
NR_148394.2:n.619_621del		non-coding transcript variant
NR_148395.2:n.883_885del		non-coding transcript variant
NR_148396.2:n.512_514del		non-coding transcript variant
NR_148397.2:n.776_778del		non-coding transcript variant
NR_148398.2:n.731_733del		non-coding transcript variant
NR_148399.2:n.1123_1125del		non-coding transcript variant
NR_148400.2:n.717_719del		non-coding transcript variant
NC_000009.12:g.131509994_131509996del
NC_000009.11:g.134385381_134385383del
NG_008896.1:g.12093_12095del
LRG_842t1:c.697_699del	LRG_842p1:p.Asn233del
LRG_842t2:c.697_699del	LRG_842p2:p.Asn233del

... more HGVS ... less HGVS

Protein change

N233del, N203del, N179del, N116del, N81del

Other names

Canonical SPDI

NC_000009.12:131509993:AAT:

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA5293373 dbSNP: rs761863400 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.
POMT1		-	-	GRCh38 GRCh37	1167	1208

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.
Limb-girdle muscular dystrophy, recessive	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000384984.5
Autosomal recessive limb-girdle muscular dystrophy type 2K	Likely pathogenic (1)	criteria provided, single submitter	Sep 24, 2024	RCV000850366.3
Autosomal recessive limb-girdle muscular dystrophy type 2K Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Walker-Warburg congenital muscular dystrophy	Uncertain significance (1)	criteria provided, single submitter	Sep 1, 2021	RCV001861343.5
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	Uncertain significance (1)	criteria provided, single submitter	Aug 28, 2019	RCV002470848.1
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	May 12, 2023	RCV003441850.5
POMT1-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Feb 15, 2023	RCV004530476.1

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.
Uncertain significance (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Limb-Girdle Muscular Dystrophy, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000477652.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Aug 28, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768638.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: A heterozygous in-frame deletion variant was identified, NM_007171.3(POMT1):c.697_699del in exon 8 of 20 of the POMT1 gene. The variant is predicted to result in an … (more) A heterozygous in-frame deletion variant was identified, NM_007171.3(POMT1):c.697_699del in exon 8 of 20 of the POMT1 gene. The variant is predicted to result in an in-frame deletion of a single amino acid at position 233 of the protein NP_009102.3(POMT1):p.(Asn233del). The asparagine at this position has low conservation (100 vertebrates, UCSC), but is located within the PMT functional domain. The variant is present in the gnomAD population database at a frequency of #% (0.0008% (2 heterozygotes; 0 homozygotes). The variant has been previously reported as a VUS (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE. (less)
Uncertain significance (Sep 01, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Walker-Warburg congenital muscular dystrophy Autosomal recessive limb-girdle muscular dystrophy type 2K Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002161308.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Comment: This variant, c.697_699del, results in the deletion of 1 amino acid(s) of the POMT1 protein (p.Asn233del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.697_699del, results in the deletion of 1 amino acid(s) of the POMT1 protein (p.Asn233del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with POMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 365275). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. (less)
Likely pathogenic (Feb 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	POMT1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004113368.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The POMT1 c.697_699delAAT variant is predicted to result in an in-frame deletion (p.Asn233del). The c.697_699delAAT nucleotides also reside at the end of exon 8 in … (more) The POMT1 c.697_699delAAT variant is predicted to result in an in-frame deletion (p.Asn233del). The c.697_699delAAT nucleotides also reside at the end of exon 8 in alternative biologically relevant POMT1 transcripts (eg. NM_001077365.2) and deletion of these nucleotides is predicted to result in defective splicing by several in silico programs (Alamut Visual Plus v1.6.1). This variant was reported in the compound heterozygous state in an individual with a POMT1-related disorder (Table S2 - Bowling et al 2022. PubMed ID: 34930662). At PreventionGenetics, we have observed the c.697_699delAAT variant with a loss-of-function variant in POMT1 in a patient with suspected dystroglycanopathy (internal data). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-134385380-CAAT-C). This variant is interpreted as likely pathogenic. (less)
Uncertain significance (May 12, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004170064.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: Observed with a pathogenic variant on the opposite allele (in trans) in a hospitalized infant in published literature, although clinical information was not provided (Bowling … (more) Observed with a pathogenic variant on the opposite allele (in trans) in a hospitalized infant in published literature, although clinical information was not provided (Bowling et al., 2022); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 34930662) (less)
Uncertain significance (Sep 27, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV004229900.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Publications: PubMed (1) PubMed: 34930662 Comment: Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is … (more) Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. (less)
Uncertain significance (Feb 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004236458.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely pathogenic (Sep 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Autosomal recessive limb-girdle muscular dystrophy type 2K Affected status: unknown Allele origin: paternal	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-SouthSeq Accession: SCV000992549.4 First in ClinVar: Sep 19, 2019 Last updated: Oct 13, 2024	Comment: ACMG codes: PM2; PM3; PM4 Clinical Features: Abnormal brain morphology (present) , Corpus callosum, agenesis of (present) , Fetal growth restriction (present) , Small for gestational age (present) , Primary microcephaly (present) … (more) Abnormal brain morphology (present) , Corpus callosum, agenesis of (present) , Fetal growth restriction (present) , Small for gestational age (present) , Primary microcephaly (present) , Hearing impairment (present) , Abnormality of the outer ear (present) , Abnormality of the face (present) , Clubfoot (present) , Central hypotonia (present) , Oligohydramnios (present) (less) Zygosity: Compound Heterozygote

Comment:

A heterozygous in-frame deletion variant was identified, NM_007171.3(POMT1):c.697_699del in exon 8 of 20 of the POMT1 gene. The variant is predicted to result in an in-frame deletion of a single amino acid at position 233 of the protein NP_009102.3(POMT1):p.(Asn233del). The asparagine at this position has low conservation (100 vertebrates, UCSC), but is located within the PMT functional domain. The variant is present in the gnomAD population database at a frequency of #% (0.0008% (2 heterozygotes; 0 homozygotes). The variant has been previously reported as a VUS (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.

Comment:

This variant, c.697_699del, results in the deletion of 1 amino acid(s) of the POMT1 protein (p.Asn233del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with POMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 365275). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

Comment:

The POMT1 c.697_699delAAT variant is predicted to result in an in-frame deletion (p.Asn233del). The c.697_699delAAT nucleotides also reside at the end of exon 8 in alternative biologically relevant POMT1 transcripts (eg. NM_001077365.2) and deletion of these nucleotides is predicted to result in defective splicing by several in silico programs (Alamut Visual Plus v1.6.1). This variant was reported in the compound heterozygous state in an individual with a POMT1-related disorder (Table S2 - Bowling et al 2022. PubMed ID: 34930662). At PreventionGenetics, we have observed the c.697_699delAAT variant with a loss-of-function variant in POMT1 in a patient with suspected dystroglycanopathy (internal data). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-134385380-CAAT-C). This variant is interpreted as likely pathogenic.

Comment:

Observed with a pathogenic variant on the opposite allele (in trans) in a hospitalized infant in published literature, although clinical information was not provided (Bowling et al., 2022); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 34930662)

Comment:

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.

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
Genome sequencing as a first-line diagnostic test for hospitalized infants.	Bowling KM	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34930662

Text-mined citations for rs761863400 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_001077365.2(POMT1):c.697_699del (p.Asn233del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs761863400 ...