Variant rs398124245 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0349 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-131523025-C-CG is Pathogenic according to our data. Variant chr9-131523025-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 3255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMT1	NM_001077365.2 linkuse as main transcript	c.2101dupG	p.Asp701fs	frameshift_variant	20/20	ENST00000402686.8	NP_001070833.1	Q9Y6A1-2A0A140VKE0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMT1	ENST00000402686.8 linkuse as main transcript	c.2101dupG	p.Asp701fs	frameshift_variant	20/20	1	NM_001077365.2	ENSP00000385797.4		Q9Y6A1-2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

31

AN:

152212

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000165

AC:

41

AN:

248716

Hom.:

0

AF XY:

0.000215

AC XY:

29

AN XY:

134636

show subpopulations

Gnomad AFR exome

AF:

0.0000629

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000233

AC:

340

AN:

1458338

Hom.:

0

Cov.:

34

AF XY:

0.000255

AC XY:

185

AN XY:

725426

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00169

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000249

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000204

AC:

31

AN:

152330

Hom.:

0

Cov.:

33

AF XY:

0.000175

AC XY:

13

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000367

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000327

Hom.:

0

Bravo

AF:

0.000219

EpiCase

AF:

0.000382

EpiControl

AF:

0.000297

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	May 26, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A1 (MIM#236670), muscular dystrophy-dystroglycanopathy (congenital with intellectual development), type B, 1 (MIM#613155) and muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 (MIM#609308). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The phenotypic spectrum ranges from the severe Walker-Warburg syndrome (WWS) to milder forms of limb girdle muscular dystrophy (LGMD) (PMID: 31311558; OMIM). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (371 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in ClinVar. It has also been detected in one infant with limb girdle muscular dystrophy and three affected fetuses with prenatal onset Walker-Warburg syndrome (PMID:31311558). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. This variant was inherited from a parent. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 24, 2015	The c.2167dupG (p.Asp723Glyfs*730) frameshift variant in the POMT1 gene has been previously reported as homozygous (Wallace SE et al., 2014; van Reeuwijk J et al., 2006) as well as compound heterozygous (BeltrÃ¡n-Valero de BernabÃ© D et al., 2002; Wallace SE et al., 2014) in patients who were diagnosed with WWS. Functional studies using a skin biopsy from a WWS patient, who was heterozygous for variant, showed that the protein's molecular weight and binding to the basement membrane ligand, laminin were all affected. Furthermore, immunofluorescence staining of a muscle biopsy from a patient, who was homozygous for this variant, showed almost complete absence of Î±-dystroglycan expression (Wallace SE et al., 2014). The frequency of this variant is absent in the 1000Genome and Exome Sequencing Project databases and is very low in ExAC (<0.1%). Finally, reputable clinical databases have classified this variant as Pathogenic. In summary, the evidence meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2024	Frameshift variant predicted to result in abnormal protein length as the last 25 amino acids are replaced with 7 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 12369018, 30060766, 22323514, 28116189, 17559086, 16575835, 24304607, 31311558, 31980526, 31127727, 24491487, 31589614, 32528171, 32860008, 35229910) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -

POMT1-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 22, 2018	The POMT1 c.2167dupG (p.Asp723GlyfsTer8) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Asp723GlyfsTer8 variant, also referred to as c.2163_2164insG, has been reported in seven studies in a total of 19 patients with POMT1-related disorders, including in two in a homozygous state, 15 in a compound heterozygous state, and two in a heterozygous state in whom a second variant was not identified (Beltran-Valero de Bernabe et al. 2002; van Reeuwijk et al. 2006; Bouchet et al. 2007; Vajsar et al. 2008; Manzini et al. 2008; Devisme et al. 2012; Wallace et al. 2014). The majority of patients were affected with Walker-Warburg syndrome or, more generally, congenital muscular dystrophy. The p.Asp723GlyfsTer8 variant was absent from 298 controls and is reported at a frequency of 0.001291 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Asp723GlyfsTer8 variant is classified as pathogenic for POMT1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 12, 2024	The POMT1 c.2167dupG variant is predicted to result in a frameshift and premature protein termination (p.Asp723Glyfs*8). This variant has been reported in the homozygous and compound heterozygous states to be causative for Walker-Warburg syndrome (Beltrán-Valero et al. 2002. PubMed ID: 12369018; Devisme et al. 2012. PubMed ID: 22323514; Wallace et al. 2014. PubMed ID: 24491487). This variant has also been reported in many unrelated individuals to be causative for a spectrum of congenital muscular dystrophies (Johnson et al. 2018. PubMed ID: 30060766; Wallace et al. 2014. PubMed ID: 24491487). This variant is reported in 0.12% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Frameshift variants in POMT1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 18, 2023

Variant summary: POMT1 c.2167dupG (p.Asp723GlyfsX8) results in a premature termination codon in the last exon affecting the last 26 amino acids of the encoded POMT1 protein. Although nonsense mediated decay is not predicted to occur, variants downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.00016 in 248716 control chromosomes. c.2167dupG has been reported in the literature in individuals affected with muscular dystrophy including Walker-Warburg syndrome (e.g. BeltranValterodeBernabe_2002). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12369018). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Abnormal brainstem morphology;C3278923:Ventriculomegaly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Institute, Tel Aviv Sourasky Medical Center

May 12, 2021

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

The c.2167dupG (p.D723Gfs*8) alteration, located in exon 20 (coding exon 19) of the POMT1 gene, consists of a duplication of G at position 2167, causing a translational frameshift with a predicted alternate stop codon after 8 amino acids. This alteration occurs at the 3' terminus of the POMT1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature. This mutation has been reported in several individuals with POMT1-related dystroglycanopathies in the homozygous and compound heterozygous state (Beltrán-Valero de Bernabé, 2002; van Reeuwijk, 2006; Manzini, 2008; Wallace, 2014; Geis, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

Muscular dystrophy-dystroglycanopathy, type C

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

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

May 02, 2023

The heterozygous p.Asp723GlyfsTer8 variant in POMT1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 502200), in one individual with muscular dystrophy. This individual also carried a variant of uncertain significance (ClinVar Variation ID: 502200), however the phase of these variants are unknown at this time. The p.Asp723GlyfsTer8 variant in POMT1 has been previously reported in more than 24 unrelated individuals with POMT1-associated muscular dystrophy-dystroglycanopathy (PMID: 31311558, PMID: 24304607, PMID: 12369018, PMID: 17559086, PMID: 18752264, PMID: 18640039, PMID: 16575835, PMID: 24491487) and segregated with disease in 11 affected relatives from 4 families (PMID: 3131155, PMID: 18640039), but has been identified in 0.06% (2/3470) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs398124245). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 24 previously reported unrelated affected individuals (PMID: 31311558, PMID: 24304607, PMID: 12369018, PMID: 17559086, PMID: 18752264, PMID: 18640039, PMID: 16575835, PMID: 24491487), 3 were homozygotes (PMID: 24491487, PMID: 16575835, PMID: 31311558), 5 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 18640039, dbSNP ID: rs1402329255; PMID: 17559086, NC_000009.12:g.131515513_131515514del; PMID: 31311558, ClinVar Variation ID: 95452, PMID: 24491487, ClinVar Variation ID: 194962), and 5 were compound heterozygotes who carried pathogenic or likely pathogenic variants in unknown phase (PMID: 24491487, ClinVar Variation ID: 1458255, 194757, 2413915, 3250, NC_000009.12:g.131504299dup), which increases the likelihood that the p.Asp723GlyfsTer8 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 3255) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 723 and leads to a premature termination codon 8 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the POMT1 gene is an established disease mechanism in autosomal recessive POMT1-associated muscular dystrophy-dystroglycanopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive POMT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1_Moderate, PM3_VeryStrong, PP1_Strong (Richards 2015). -

Autosomal recessive limb-girdle muscular dystrophy type 2K;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

This sequence change creates a premature translational stop signal (p.Asp723Glyfs*8) in the POMT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the POMT1 protein. This variant is present in population databases (rs767631573, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with congenital muscular dystrophy and/or Walker-Warburg syndrome (PMID: 12369018, 16575835, 17559086, 22323514, 24304607, 24491487). This variant is also known as c.2167InsG, c.2167_2168insG, and p.G722fs. ClinVar contains an entry for this variant (Variation ID: 3255). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs398124245

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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