9-131513243-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001077365.2(POMT1):c.1087C>T(p.Gln363*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

POMT1
NM_001077365.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.44

Publications

8 publications found

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]

POMT1 Gene-Disease associations (from GenCC):

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp
myopathy caused by variation in POMT1
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal recessive limb-girdle muscular dystrophy type 2K
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy with cerebellar involvement
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy with intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy without intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscle-eye-brain disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscular dystrophy-dystroglycanopathy, type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

POMT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-131513243-C-T is Pathogenic according to our data. Variant chr9-131513243-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 95452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMT1	NM_001077365.2 link	c.1087C>T	p.Gln363*	stop_gained	Exon 12 of 20	ENST00000402686.8	NP_001070833.1	Q9Y6A1-2A0A140VKE0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMT1	ENST00000402686.8 link	c.1087C>T	p.Gln363*	stop_gained	Exon 12 of 20	1	NM_001077365.2	ENSP00000385797.4		Q9Y6A1-2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000361

AC:

AN:

249572

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000799

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000671

AC:

AN:

1460772

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000854

AC:

AN:

1111938

Other (OTH)

AF:

0.0000497

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41522

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000634

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Nov 04, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28116189, 30454682, 12369018, 31311558) -

Jul 14, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:2

Feb 09, 2023

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The inherited c.1087C>T, p.(Gln363Ter) variant (annotation based on MANE Select transcript NM_001077365.2) identified in the POMT1 gene is a nonsense variant predicted to lead to the premature termination of the protein at amino acid 363/726 (exon 12/20) and is expected to lead to the loss of protein function via nonsense mediated decay. This variant is found with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) with highest allele frequency of 4.53e-5 (BRAVO-TOPMed, 12 heterozygotes, 0 homozygotes), suggesting it is not a common benign variant in the populations represented in those databases. The c.1087C>T, p.(Gln363Ter) variant is reported in ClinVar as Pathogenic (VarID:95452; 2 stars, 7 submissions, no conflicts) and has been reported in individuals in the literature with Walker-Warburg syndrome in both homozygous state [PMID:12369018], and in compound heterozygosity with a second pathogenic variant [PMID:15522202] (reported as c.1153C>T (p.(Gln385Ter) as annotated from transcript NM_007171). Given its deleterious nature, low frequency in population databases, and observation in affected individuals in the literature in homozygosity and in compound heterozygosity with a second pathogenic variant, the inherited c.1087C>T, p.(Gln363Ter) variant is reported as Pathogenic. -

Jun 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:2

Nov 28, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) 0202 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction), but is located in an exon that may undergo alternative splicing. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (110 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 reported in three affected fetuses with prenatal onset Walker-Warburg syndrome (PMID: 31311558). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

May 07, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: POMT1 c.1153C>T (p.Gln385X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.6e-05 in 249572 control chromosomes. c.1153C>T has been reported in the literature in homozygous twins affected with Walker-Warburg syndrome (e.g. Beltran-Valero_2002). These data indicate that the variant may be associated with disease. 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). ClinVar contains an entry for this variant (Variation ID: 95452). Based on the evidence outlined above, the variant was classified as pathogenic. -

Limb-girdle muscular dystrophy due to POMK deficiency

Pathogenic:1

May 18, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

Pathogenic:1

Dec 13, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln385*) in the POMT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POMT1 are known to be pathogenic (PMID: 12369018, 15637732, 16575835). This variant is present in population databases (rs200056620, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with Walker-Warburg syndrome (PMID: 12369018, 28116189, 31311558). ClinVar contains an entry for this variant (Variation ID: 95452). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

PhyloP100

2.4

Vest4

0.86

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over