rs398124245

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The ENST00000402686.8(POMT1):​c.2101dup​(p.Asp701GlyfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,610,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y699Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

POMT1
ENST00000402686.8 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 9.60
Variant links:
Genes affected
POMT1 (HGNC:9202): (protein O-mannosyltransferase 1) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT2 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS) and limb-girdle muscular dystrophy type 2K (LGMD2K). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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. There are 12 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
POMT1NM_001077365.2 linkuse as main transcriptc.2101dup p.Asp701GlyfsTer8 frameshift_variant 20/20 ENST00000402686.8 NP_001070833.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POMT1ENST00000402686.8 linkuse as main transcriptc.2101dup p.Asp701GlyfsTer8 frameshift_variant 20/201 NM_001077365.2 ENSP00000385797 P1Q9Y6A1-2

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 providedliterature onlyOMIMMay 26, 2009- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityJul 24, 2015The 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 (Beltrán-Valero de Bernabé 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 α-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 submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2016This variant was classified as: Pathogenic. This variant was inherited from a parent. -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease Company-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 30, 2024- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteOct 10, 2024Based 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 -
not provided Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 22, 2024Frameshift 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 submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 07, 2017- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 02, 2015- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 27, 2023- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2017- -
POMT1-related disorder Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 12, 2024The 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. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaAug 22, 2018The 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. -
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 18, 2023Variant 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 submitterclinical testingGenetics Institute, Tel Aviv Sourasky Medical CenterMay 12, 2021- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 07, 2022The 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 (Beltr&aacute;n-Valero de Bernab&eacute;, 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 submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardMay 02, 2023The 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’s 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 03, 2024This 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.

Other links and lift over

dbSNP: rs398124245; hg19: chr9-134398412; API