ClinVar Miner

Submissions for variant NM_003494.3(DYSF):c.3113G>A (rs150877497)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000493116 SCV000780666 likely pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000493116 SCV000701408 pathogenic not provided 2017-04-03 criteria provided, single submitter clinical testing
GeneDx RCV000493116 SCV000582561 pathogenic not provided 2018-01-22 criteria provided, single submitter clinical testing The R1038Q pathogenic variant has been previously observed in multiple unrelated individuals with DYSF-related disorders, who harbored an additional DYSF variant, referred for genetic testing at GeneDx and in the published literature (Cagliani et al., 2003; Krahn et al., 2009). Western blot analysis and immunohistochemistry demonstrated individuals harboring R1038Q had reduced dysferlin (Cagliani et al., 2003; Xi et al., 2014; Nagaraju et al., 2008). The R1038Q variant is observed in 11/111,482 (0.01%) alleles from individuals of European background (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, we interpret R1038Q as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000555598 SCV000914939 pathogenic Dysferlinopathy 2017-04-28 criteria provided, single submitter clinical testing The DYSF c.3113G>A (p.Arg1038Gln) variant has been reported in at least six studies and is found in a total of nine patients with dysferlinopathy, including one homozygote, four presumed compound heterozygotes, one patient where four other variants in this gene were also identified, one heterozygote, and two patients in whom the genotypes were not specified (Cagliani et al. 2003; Nagaraju et al. 2008; Krahn et al. 2009; Xi et al. 2014; Shin et al. 2015 and Quinn et al. 2016). The p.Arg1038Gln variant was absent from 300 control chromosomes and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of protein from muscle tissue revealed 4% residual dysferlin compared to wild type (Cagliani et al. 2003). Based on the collective evidence, the p.Arg1038Gln variant is classified as pathogenic for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000555598 SCV000649653 likely pathogenic Dysferlinopathy 2017-04-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1038 of the DYSF protein (p.Arg1038Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs150877497, ExAC 0.02%). This variant has been reported in individuals and families affected with one of the autosomal recessive conditions of either limb-girdle muscular dystrophy type 2 (LGMD2), Miyoshi myopathy (MM), or DYSF-deficiency associated with exercise intolerance. In the majority of these cases, this variant occurs with a second pathogenic variant in DYSF, which suggests the c.3113G>A substitution may contribute to disease (PMID: 14678801, 18853459, 18832576, 25591676). ClinVar contains an entry for this variant (Variation ID: 224664). In several cases, biopsied muscle tissue from affected patients carrying this variant along with a second pathogenic DYSF variant were found to be devoid of DYSF protein expression by immunohistochemistry and/or western blot (PMID: 18276788, 25591676). In summary, this variant is a rare missense change that has been identified in the population and in affected individuals. The co-occurrence of this variant with additional pathogenic truncating DYSF variants in affected individuals lacking DYSF protein expression suggests this variant contributes to disease. However, additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000596380 SCV000803534 likely pathogenic Limb-girdle muscular dystrophy, type 2B 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy, limb-girdle, type 2B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:18276788). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:18276788) (PMID:14678801).

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