ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.5546G>A (p.Arg1849Lys) (rs786205084)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000007073 SCV000255773 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2013-03-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723469 SCV000331116 pathogenic not provided 2016-08-09 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000007073 SCV001164542 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2018-12-03 criteria provided, single submitter research The homozygous p.Arg1849Lys variant in DYSF (sometimes called p.Gly1802ValfsX17 due to its splicing effect) was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD) (LGMD). This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Arg1849Lys variant in DYSF has been reported in 7 Portuguese individuals with LGMD, including one individual compound heterozygous with this variant and a second variant not reported in ClinVar, c.5657delG (PMID: 20535123). In vitro functional studies with peripheral blood and muscle tissue from 7 unrelated individuals with LGMD and this variant (6 homozygous, 1 heterozygous) provide some evidence that the p.Arg1849Lys variant may impact protein function. Transcript analysis demonstrated an abnormal lack of splicing Exon 49, resulting in a reading frameshift and early termination of the protein (PMID: 20535123). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PP3 (Richards 2015).
Invitae RCV001215439 SCV001387185 pathogenic Qualitative or quantitative defects of dysferlin 2019-06-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1810 of the DYSF protein (p.Arg1810Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 48 of the DYSF coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of limb-girdle muscular dystrophy (PMID: 20535123, Invitae). This variant is also known as c.5492G>A and c.5525G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 18443). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 25312915, 20535123). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007073 SCV000027269 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2010-08-01 no assertion criteria provided literature only

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