rs1258728780
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_001130987.2(DYSF):c.992G>A(p.Gly331Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,010 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G331R) has been classified as Pathogenic.
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.992G>A | p.Gly331Glu | missense_variant | 10/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.896G>A | p.Gly299Glu | missense_variant | 9/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.992G>A | p.Gly331Glu | missense_variant | 10/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.896G>A | p.Gly299Glu | missense_variant | 9/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461846Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727238
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
Qualitative or quantitative defects of dysferlin Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 24, 2023 | This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 299 of the DYSF protein (p.Gly299Glu). This missense change has been observed in individual(s) with Miyoshi myopathy (PMID: 16010686, 33610434). ClinVar contains an entry for this variant (Variation ID: 552632). 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. This variant disrupts the p.Gly299 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17698709, 18306167, 23185377, 27647186, 28877744). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Likely pathogenic, criteria provided, single submitter | research | Jain Foundation | Mar 13, 2023 | This variant is rare with an allele frequency of 0.0065%. This variant has been reported in individuals suspected to have Dysferlinopathy (PMID: 36983702, 16010686, 18853459, 27602406, 33927379), but only in one case was it found in conjunction with a DYSF variant that was considered likely pathogenic (p.1168G>A - PMID: 36983702). In all the other cases the second DYSF variant was labeled as a VUS. This variant disrupts the p.Gly299 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (p.Gly299Arg - PMID: 27647186 and p.Gly299Trp - PMID: 18306167). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 (0.947) and CADD (25.2) scores support a deleterious effect. The ACMG classification criteria are: PM2 moderate, PM5 strong, PP3, and PS3 supporting. Based on the above data, this variant has been classified as Likely Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2022 | Variant summary: DYSF c.896G>A (p.Gly299Glu) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.896G>A has been reported in the literature in individuals affected with dysferlinopathy, noted with reduced protein expression in muscle biopsies, however a 2nd pathogenic variant could not be identified in any of them (Nguyen_2005, Krahn_2009, Harris_2016, Charnay_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 27, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at