Submissions for variant NM_001130987.2(DYSF):c.5420G>A (p.Arg1807Gln)

gnomAD frequency: 0.00003  dbSNP: rs148860301

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725114	SCV000334179	uncertain significance	not provided	2015-08-20	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000266653	SCV000613214	uncertain significance	not specified	2017-02-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001141002	SCV001301313	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001141002	SCV001577676	pathogenic	Qualitative or quantitative defects of dysferlin	2024-09-27	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 1768 of the DYSF protein (p.Arg1768Gln). This variant is present in population databases (rs148860301, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of DYSF-related conditions (PMID: 31475473, 32751317; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 282624). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DYSF protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1768 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17070050, 17698709, 18853459, 25591676, 25783436, 27647186). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV001810440	SCV002060044	uncertain significance	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2021-11-16	criteria provided, single submitter	clinical testing	NM_003494.3(DYSF):c.5303G>A(R1768Q) is a missense variant classified as a variant of uncertain significance in the context of dysferlinopathy. R1768Q has been observed in cases with relevant disease (PMID: 31475473, 33927379). Functional assessments of this variant are not available in the literature. R1768Q has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, there is insufficient evidence to classify NM_003494.3(DYSF):c.5303G>A(R1768Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV000725114	SCV003829621	uncertain significance	not provided	2019-04-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463743	SCV004196506	likely pathogenic	Miyoshi muscular dystrophy 1	2024-01-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001810440	SCV005659336	likely pathogenic	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2024-02-13	criteria provided, single submitter	clinical testing
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000757894	SCV000882754	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2019-02-11	no assertion criteria provided	research	The proband has another variant, NG_011618.3: c.1284+2T>C.