rs119462982
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001077365.2(POMT1):āc.598G>Cā(p.Ala200Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,894 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 Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000055 ( 0 hom. )
Consequence
POMT1
NM_001077365.2 missense
NM_001077365.2 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 2.57
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.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 9-131509801-G-C is Pathogenic according to our data. Variant chr9-131509801-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131509801-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POMT1 | NM_001077365.2 | c.598G>C | p.Ala200Pro | missense_variant | 7/20 | ENST00000402686.8 | NP_001070833.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251496Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135922
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727248
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2K Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003243, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.831, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jan 03, 2024 | PM2, PM3, PP3, PP5 - Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. This variant has been previously reported as causative for Muscular dystrophy. (PMID:31311558). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2005 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 27, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | POMT1: PM3:Very Strong, PM2 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 01, 2023 | - - |
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 | May 03, 2023 | Variant summary: POMT1 c.598G>C (p.Ala200Pro) results in a non-conservative amino acid change located in the Glycosyl transferase family 39/83 domain (IPR003342) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251496 control chromosomes (gnomAD). c.598G>C has been reported in the literature in multiple homozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Geis_2019). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 31311558). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 01, 2020 | Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS4_Moderate,PM2,PM3 - |
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 | Jul 25, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMT1 protein function. ClinVar contains an entry for this variant (Variation ID: 3243). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 15792865, 28097321, 30426380). This variant is present in population databases (rs119462982, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 200 of the POMT1 protein (p.Ala200Pro). - |
Abnormality of the nervous system Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;D;.;D;.;D;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;.;H;H;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;T;T
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;.;D;D;.;.
Vest4
MutPred
0.93
.;Loss of stability (P = 0.0656);.;.;Loss of stability (P = 0.0656);Loss of stability (P = 0.0656);.;.;
MVP
MPC
1.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at