Submissions for variant NM_001130987.2(DYSF):c.4079G>A (p.Arg1360Gln)

gnomAD frequency: 0.00003  dbSNP: rs747583441

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000266196	SCV000345268	uncertain significance	not provided	2016-09-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000343174	SCV000431812	uncertain significance	Miyoshi myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000392904	SCV000431813	uncertain significance	Limb-Girdle Muscular Dystrophy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001140152	SCV001300373	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.
Invitae	RCV001140152	SCV003024362	likely pathogenic	Qualitative or quantitative defects of dysferlin	2023-09-22	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with DYSF-related conditions. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1342 of the DYSF protein (p.Arg1342Gln). This variant is present in population databases (rs747583441, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 290670). 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. This variant disrupts the p.Arg1342 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21522182). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000266196	SCV003831347	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003380540	SCV004090491	uncertain significance	Inborn genetic diseases	2023-08-21	criteria provided, single submitter	clinical testing	The c.4025G>A (p.R1342Q) alteration is located in exon 38 (coding exon 38) of the DYSF gene. This alteration results from a G to A substitution at nucleotide position 4025, causing the arginine (R) at amino acid position 1342 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.