Submissions for variant NM_001130987.2(DYSF):c.2697+1G>A

gnomAD frequency: 0.00046  dbSNP: rs140108514

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000176550	SCV000247241	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2014-10-02	criteria provided, single submitter	clinical testing
Center for Genetic Medicine Research, Children's National Medical Center	RCV000233433	SCV000265772	likely pathogenic	Miyoshi muscular dystrophy 1	2015-12-01	criteria provided, single submitter	research
GeneDx	RCV000080255	SCV000329662	pathogenic	not provided	2022-01-28	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Published minigene assays show that this canonical splice variant results in the skipping of exon 25, suggesting that it results in abnormal splicing (Kergourlay et al., 2014); This variant is associated with the following publications: (PMID: 22246893, 25525159, 23243261, 12796534, 11532985, 18853459, 29382405, 31980526, 31589614, 33610434, 24438169, 25312915)
Eurofins Ntd Llc (ga)	RCV000080255	SCV000337922	pathogenic	not provided	2016-06-09	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000080255	SCV000613194	pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, including cases of Miyoshi myopathy and limb girdle muscular dystrophy, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant is also referred to as c.2697+1G>A and c.3016+1G>A in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown to cause exon skipping (PMID: 25312915).
Invitae	RCV000697172	SCV000825769	pathogenic	Qualitative or quantitative defects of dysferlin	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 25 of the DYSF gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs140108514, gnomAD 0.2%). Disruption of this splice site has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy and Miyoshi myopathy (PMID: 12796534, 18853459, 21816046, 22246893, 23243261, 27854218). This variant is also known as G3016+1A and c.3016+1G>A. ClinVar contains an entry for this variant (Variation ID: 94291). Studies have shown that disruption of this splice site results in skipping of exon 25, but is expected to preserve the integrity of the reading-frame (PMID: 25312915). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763504	SCV000894294	pathogenic	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2018-10-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000176550	SCV001164531	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2018-12-03	criteria provided, single submitter	research	The heterozygous c.2697+1G>A variant in DYSF was identified by our study in one individual in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.1706% (41/24026) of African chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140108514). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The c.2697+1G>A variant in DYSF has been reported in 3 individuals with LGMD (PMID: 23243261). The presence of this variant in combination with reported pathogenic variants and in 2 individuals with LGMD increases the likelihood that the c.2697+1G>A variant is pathogenic. In vitro functional studies provide some evidence that the c.2697+1G>A variant may impact protein function by causing abnormal splicing of Exon 25 (PMID: 25312915). However, these types of assays may not accurately represent biological function.This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an in-frame transcript deletion and abnormal or absent protein. Loss of function In the DYSF gene is an established disease mechanism in autosomal recessive LGMD. In summary, the clinical significance of the 2697+1G>A variant is pathogenic. ACMG/AMP Criteria applied: PVS1_Moderate, PS3, PM3_Strong (Richards 2015).
Myriad Genetics, Inc.	RCV000763504	SCV001193993	pathogenic	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2021-10-01	criteria provided, single submitter	clinical testing	NM_003494.3(DYSF):c.2643+1G>A is a canonical splice variant classified as pathogenic in the context of dysferlinopathy. c.2643+1G>A has been observed in cases with relevant disease (PMID: 30564623, 12796534, 23243261, 27854218, 18832576, 24488599, 21816046). Functional assessments of this variant are available in the literature (PMID: 25312915). c.2643+1G>A has been observed in population frequency databases (gnomAD: AFR 0.13%). In summary, NM_003494.3(DYSF):c.2643+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV000080255	SCV002021868	pathogenic	not provided	2023-08-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000080255	SCV002520079	pathogenic	not provided	2021-07-27	criteria provided, single submitter	clinical testing	PM2, PS4_moderate, PVS1
PreventionGenetics, part of Exact Sciences	RCV003415848	SCV004117853	pathogenic	DYSF-related disorder	2023-04-26	criteria provided, single submitter	clinical testing	The DYSF c.2643+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in patients diagnosed with limb-girdle muscular dystrophy type 2B (LGMD2B) or Miyoshi myopathy (Krahn et al. 2009. PubMed ID: 18853459; Takahashi et al. 2013. PubMed ID: 23243261). In a mini-gene assay, the c.2643+1G>A variant led to exon skipping (Kergourlay et al. 2014. PubMed ID: 25312915). This variant has been reported at an allele frequency of ~0.2% in an African population; in other ethnicities it is absent or reported less frequently (i.e. <0.01%) (http://gnomad.broadinstitute.org/variant/2-71795213-G-A). Variants that disrupt the consensus splice donor site in DYSF are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000233433	SCV004194176	pathogenic	Miyoshi muscular dystrophy 1	2023-10-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000176550	SCV001458659	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-09-16	no assertion criteria provided	clinical testing