rs766341386
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001130987.2(DYSF):βc.3570_3571delβ(p.Ser1191Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.000012 ( 0 hom. )
Consequence
DYSF
NM_001130987.2 frameshift
NM_001130987.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.60
Genes affected
DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 2-71590280-CTT-C is Pathogenic according to our data. Variant chr2-71590280-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 217226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71590280-CTT-C is described in Lovd as [Pathogenic]. Variant chr2-71590280-CTT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.3570_3571del | p.Ser1191Ter | frameshift_variant | 32/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.3516_3517del | p.Ser1173Ter | frameshift_variant | 32/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000258104.8 | c.3516_3517del | p.Ser1173Ter | frameshift_variant | 32/55 | 1 | NM_003494.4 | A1 | |
DYSF | ENST00000410020.8 | c.3570_3571del | p.Ser1191Ter | frameshift_variant | 32/56 | 1 | NM_001130987.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251460Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135896
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461872Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 727234
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 10, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 19, 2021 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 06, 2012 | - - |
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 | Feb 20, 2023 | Variant summary: DYSF c.3516_3517delTT (p.Ser1173X) 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 2.4e-05 in 251460 control chromosomes (gnomAD). c.3516_3517delTT has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Rosales_2010, Zhong_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as 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 | Dec 23, 2023 | - - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change creates a premature translational stop signal (p.Ser1173*) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs763230414, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with dysferlinopathy (PMID: 16010686, 17562833, 17698709, 20544924, 21522182, 22616201, 25591676, 27229680, 27858744, 28403181). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 217226). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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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