Submissions for variant NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln)

gnomAD frequency: 0.00001  dbSNP: rs150877497

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555598	SCV000649653	pathogenic	Qualitative or quantitative defects of dysferlin	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1038 of the DYSF protein (p.Arg1038Gln). This variant is present in population databases (rs150877497, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 14678801, 18832576, 18853459, 25591676, 27821570). This variant is also known as p.Arg1056Gln. ClinVar contains an entry for this variant (Variation ID: 242418). 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. Experimental studies have shown that this missense change affects DYSF function (PMID: 27821570). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000493116	SCV000701408	pathogenic	not provided	2017-04-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000493116	SCV000780666	likely pathogenic	not provided	2017-12-01	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000596380	SCV000803534	likely pathogenic	Autosomal recessive 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).
Illumina Laboratory Services, Illumina	RCV000555598	SCV000914939	pathogenic	Qualitative or quantitative defects of dysferlin	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196058	SCV001366487	likely pathogenic	Distal myopathy with anterior tibial onset	2019-03-21	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. This variant was detected in homozygous state.
Revvity Omics, Revvity	RCV000493116	SCV002021878	pathogenic	not provided	2021-12-07	criteria provided, single submitter	clinical testing
3billion	RCV000596380	SCV003841344	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000242418). A different missense change at the same codon (p.Arg1056Pro) has been reported to be associated with DYSF related disorder (PMID: 33610434). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV003469174	SCV004194203	pathogenic	Miyoshi muscular dystrophy 1	2024-02-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000596380	SCV001132178	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2017-11-02	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000493116	SCV002035547	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000493116	SCV002037438	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000596380	SCV002082260	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-08-12	no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV001196058	SCV005091514	likely pathogenic	Distal myopathy with anterior tibial onset	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team