Submissions for variant NM_001130987.2(DYSF):c.3778C>T (p.Arg1260Cys)

gnomAD frequency: 0.00016  dbSNP: rs369170272

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000401895	SCV000431796	uncertain significance	Limb-Girdle Muscular Dystrophy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000304009	SCV000431797	uncertain significance	Miyoshi myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000684979	SCV000812447	uncertain significance	Qualitative or quantitative defects of dysferlin	2022-04-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1242 of the DYSF protein (p.Arg1242Cys). This variant is present in population databases (rs369170272, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 336966). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Illumina Laboratory Services, Illumina	RCV000684979	SCV001303109	uncertain significance	Qualitative or quantitative defects of dysferlin	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001764307	SCV001991476	uncertain significance	not provided	2019-07-29	criteria provided, single submitter	clinical testing	Previously reported as a variant of uncertain significance in a patient with a clinical diagnosis of congenital myopathy who also harbored a second DYSF variant; however, parental studies were not reported (Savarese et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25214167)
Athena Diagnostics	RCV001764307	SCV004229608	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Natera, Inc.	RCV001276449	SCV001462796	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-09-16	no assertion criteria provided	clinical testing