chr9-131521351-G-C
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001077365.2(POMT1):āc.1704G>Cā(p.Gln568His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,872 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001077365.2 missense
Scores
Clinical Significance
Conservation
Publications
- muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp
- myopathy caused by variation in POMT1Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- autosomal recessive limb-girdle muscular dystrophy type 2KInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- congenital muscular dystrophy with cerebellar involvementInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- congenital muscular dystrophy with intellectual disabilityInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- congenital muscular dystrophy without intellectual disabilityInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- muscle-eye-brain diseaseInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- muscular dystrophy-dystroglycanopathy, type AInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POMT1 | NM_001077365.2 | c.1704G>C | p.Gln568His | missense_variant | Exon 18 of 20 | ENST00000402686.8 | NP_001070833.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251458 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727236 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Pathogenic:1
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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
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 3246). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 16575835, 16717220, 18513969). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs119462986, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 590 of the POMT1 protein (p.Gln590His). -
not provided Pathogenic:1
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not specified Uncertain:1
Variant summary: POMT1 c.1770G>C (p.Gln590His) results in a non-conservative amino acid change located in the Protein O-mannosyl-transferase, C-terminal four TM domain (IPR032421) 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 4e-06 in 251458 control chromosomes. c.1770G>C has been reported in the literature in compound heterozygous individuals affected with congenital muscular dystrophy with intellectual disability (e.g. vanReeuwijk_2006, Messina_2008). 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 publications have been ascertained in the context of this evaluation (PMID: 18513969, 16575835). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at