Submissions for variant NM_001130987.2(DYSF):c.2477G>A (p.Arg826Gln)

gnomAD frequency: 0.00041  dbSNP: rs35297901

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000356959	SCV000336402	uncertain significance	not provided	2018-01-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000366269	SCV000431761	uncertain significance	Limb-girdle muscular dystrophy, recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000271598	SCV000431762	uncertain significance	Miyoshi myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000695150	SCV000823632	likely benign	Qualitative or quantitative defects of dysferlin	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000695150	SCV001300951	uncertain significance	Qualitative or quantitative defects of dysferlin	2018-01-12	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	RCV000356959	SCV001780133	uncertain significance	not provided	2020-11-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In addition, in silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported previously in the heterozygous state as a variant of uncertain significance in two individuals with limb-girdle muscular dystrophy (Nallamilli et al., 2018); This variant is associated with the following publications: (PMID: 32528171, 30564623)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001271793	SCV002768490	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Miyoshi muscular dystrophy 1 (MIM#254130), muscular dystrophy, limb-girdle, autosomal recessive 2 (MIM#253601) and myopathy, distal, with anterior tibial onset (MIM#606768). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 105 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated FerB domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS in individuals with proximal muscle weakness or limb girdle muscular dystrophy, either with an unspecified zygosity or as single hits (PMID: 30564623, 32528171). This variant is also consistently classified as a VUS by diagnostic laboratories in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002487214	SCV002782740	uncertain significance	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2022-05-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000356959	SCV003831341	uncertain significance	not provided	2021-11-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001271793	SCV001453233	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-01-01	no assertion criteria provided	clinical testing