Submissions for variant NM_001130987.2(DYSF):c.3886C>T (p.Gln1296Ter)

gnomAD frequency: 0.00003  dbSNP: rs727503911

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000323235	SCV000331597	pathogenic	not provided	2017-04-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809801	SCV000949977	pathogenic	Qualitative or quantitative defects of dysferlin	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1278*) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs727503911, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with distal myopathy (PMID: 16010686, 17698709, 25135358). ClinVar contains an entry for this variant (Variation ID: 167025). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000984259	SCV001430649	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-06-16	criteria provided, single submitter	clinical testing	This DYSF variant (rs727503911) is rare (<0.1%) in a large population dataset4 (gnomAD: 4/279112 total alleles; 0.0014%; no homozygotes) and has an entry in ClinVar. This variant has been reported previously in a homozygous or compound heterozygous state in individuals affected with LGMDR2 or MMD1. This nonsense variant results in a premature stop codon in exon 34 of 56 likely leading to nonsense?mediated decay and lack of protein production. We consider this variant to be pathogenic.
Revvity Omics, Revvity	RCV000323235	SCV002021862	pathogenic	not provided	2021-05-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492572	SCV002781083	pathogenic	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2021-07-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000323235	SCV004154967	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	DYSF: PVS1, PM2, PM3
Baylor Genetics	RCV003467211	SCV004194175	pathogenic	Miyoshi muscular dystrophy 1	2024-03-13	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000984259	SCV005373711	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2023-05-20	criteria provided, single submitter	clinical testing	The observed stop gained c.3886C>T(p.Gln1296Ter) variant in DYSF gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with limb-girdle muscular dystrophies (LGMD2) (Stehlíková et al., 2014; Rufibach et al., 2023). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (Nguyen et al., 2007). Computational evidence (MutationTaster - Disease causing automatic) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000984259	SCV001132383	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2016-11-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000984259	SCV001462798	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917498	SCV004736704	pathogenic	DYSF-related disorder	2023-11-14	no assertion criteria provided	clinical testing	The DYSF c.3832C>T variant is predicted to result in premature protein termination (p.Gln1278*). This variant was reported in individuals with DYSF-related muscular dystrophy (Nguyen et al 2005. PubMed ID: 16010686; Klinge et al 2009. PubMed ID: 19528035; Moore et al 2021. PubMed ID: 33610434; Stehlíková et al 2014. PubMed ID: 25135358). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-71827961-C-T). Nonsense variants in DYSF are expected to be pathogenic. This variant is interpreted as pathogenic.