2-71656237-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_001130987.2(DYSF):c.4702C>T(p.Arg1568Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,172 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 Uncertain significance (★★).
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.4702C>T | p.Arg1568Trp | missense_variant | Exon 43 of 56 | 1 | NM_001130987.2 | ENSP00000386881.3 | ||
DYSF | ENST00000258104.8 | c.4585C>T | p.Arg1529Trp | missense_variant | Exon 42 of 55 | 1 | NM_003494.4 | ENSP00000258104.3 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152170Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251482Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135912
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 727244
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152288Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74468
ClinVar
Submissions by phenotype
not provided Uncertain:2
DYSF: PM2, PP3 -
Reported in a patient with LGMD in published literature (Guglieri et al., 2008); 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: 17994539) -
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:2
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not specified Uncertain:1
Variant summary: DYSF c.4585C>T (p.Arg1529Trp) 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 3.6e-05 in 251482 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4585C>T has been reported as a single change in DYSF in one individual affected with Limb-Girdle Muscular Dystrophy,2B, without strong evidence for causality (example, Guglieri_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 17994539). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
See cases Uncertain:1
ACMG classification criteria: PP3 -
Qualitative or quantitative defects of dysferlin Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1529 of the DYSF protein (p.Arg1529Trp). This variant is present in population databases (rs375698433, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb girdle muscular dystrophy, type 2B (PMID: 17994539). ClinVar contains an entry for this variant (Variation ID: 538620). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at