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

dbSNP: rs786205084

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000007073	SCV000255773	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2013-03-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000723469	SCV000331116	pathogenic	not provided	2016-08-09	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215439	SCV001387185	pathogenic	Qualitative or quantitative defects of dysferlin	2024-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1810 of the DYSF protein (p.Arg1810Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of limb-girdle muscular dystrophy (PMID: 20535123; Invitae). This variant is also known as c.5492G>A and c.5525G>A. ClinVar contains an entry for this variant (Variation ID: 18443). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 49 and introduces a premature termination codon (PMID: 20535123). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002476993	SCV002778234	pathogenic	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2024-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000007073	SCV000027269	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2010-08-01	no assertion criteria provided	literature only