rs746243052
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001130987.2(DYSF):โc.5419C>Tโ(p.Arg1807Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,038 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 (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1807Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.5419C>T | p.Arg1807Trp | missense_variant | 48/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.5302C>T | p.Arg1768Trp | missense_variant | 47/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.5419C>T | p.Arg1807Trp | missense_variant | 48/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.5302C>T | p.Arg1768Trp | missense_variant | 47/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251232Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135836
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727222
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 08, 2022 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, including cases of Miyoshi myopathy and limb girdle muscular dystrophy, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 03, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 29, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 2021 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16996541, 25783436, 25591676, 33715265, 32400077, Fedotov2016[casereport], 21522182, 31407473, 18853459, 17070050, 32528171, 27647186, 17698709, 29792937, 18808059, 33610434, 25046369, 32576226) - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 04, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU Mรผnchen | Jan 04, 2019 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
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 | Jan 24, 2023 | Variant summary: DYSF c.5302C>T (p.Arg1768Trp) results in a non-conservative amino acid change in 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 251232 control chromosomes. c.5302C>T has been reported in the literature as a biallelic homozygous or compound heterozygous genotype in multiple individuals affected with features of Miyoshi Myopathy/Limb-Girdle Muscular Dystrophy, Autosomal Recessive 2B (example, PMID: 21522182, 17070050, 33715265). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1768 of the DYSF protein (p.Arg1768Trp). This variant is present in population databases (rs746243052, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of dysferlinopathies (PMID: 17070050, 17698709, 18853459, 25591676, 25783436, 27647186). ClinVar contains an entry for this variant (Variation ID: 286151). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at