rs727503910
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001130987.2(DYSF):c.2844G>C(p.Trp948Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.2844G>C | p.Trp948Cys | missense_variant | 26/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.2790G>C | p.Trp930Cys | missense_variant | 26/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.2844G>C | p.Trp948Cys | missense_variant | 26/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.2790G>C | p.Trp930Cys | missense_variant | 26/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 36
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Qualitative or quantitative defects of dysferlin Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Jain Foundation | Mar 13, 2023 | This variant is absent from gnomAD v2.1.1. This variant has been reported in individuals with a clinical phenotype consistent with dysferlinopathy, associated with disease range dysferlin protein levels, and found in the heterozygous state in conjuction with the pathogeic or likely pathogenic DYSF variants, c.2643+1G>A, c.4024C>T, or c.3832C>T (PMID: 36983702, 18853459). This variant has also been reported to cause reduced dysferlin protein expression and no plasma membrane localization via an in vitro assay (PMID: 35028538). Both the REVEL (0.867) and CADD (25.7) scores support a deleterious effect. The ACMG classification criteria applied are: PM2 moderate, PM3 moderate, PP3, PP4 moderate, and PS3 supporting. Based on the above data, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 930 of the DYSF protein (p.Trp930Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 18853459, 33610434). ClinVar contains an entry for this variant (Variation ID: 167021). 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) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 18, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 05, 2016 | - - |
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 09, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 03, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at