Submissions for variant NM_001130987.2(DYSF):c.1693-6T>A

gnomAD frequency: 0.00001  dbSNP: rs886039573

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254712	SCV000322446	pathogenic	not provided	2017-08-31	criteria provided, single submitter	clinical testing	The c.1639-6T>A pathogenic variant in the DYSF gene has been reported previously in association with DYSF-related disorders when present in the homozygous state or when seen with another variant (Kesper et al., 2009; Ankala et al., 2014; Cacciottolo et al., 2011). Functional studies demonstrate the use of a cryptic acceptor site of intron 19 that results in the retention of 4 base pairs of intronic DNA, which is predicted to result in a truncated protein (Cacciottolo et al., 2011; Kergourlay et al., 2014). The c.1639-6T>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1639-6T>A as a pathogenic variant.
Eurofins Ntd Llc (ga)	RCV000254712	SCV000706720	pathogenic	not provided	2018-03-20	criteria provided, single submitter	clinical testing
Invitae	RCV001381504	SCV001579931	pathogenic	Qualitative or quantitative defects of dysferlin	2023-08-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in insertion of 4 nucleotides from intron 18 and introduces a premature termination codon (PMID: 21522182, 25312915). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 265488). This variant has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 19154541, 21522182, 24488599, 30919934). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 18 of the DYSF gene. It does not directly change the encoded amino acid sequence of the DYSF protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Jain Foundation	RCV001381504	SCV003927998	pathogenic	Qualitative or quantitative defects of dysferlin	2023-03-13	criteria provided, single submitter	research	This variant has been observed in individuals with clinical features of dysferlinopathy in both the homozygous state (PMID: 21522182) and in the heterzygous state in conjunction with another pathogenic DYSF variant c.5503A>G (PMID:30564623, 36983702). It has also been identified in one family with dysferlinopathy, segregating with the disease in 2 affected siblings, and was associated with absent dysferlin protein expression (PMID:36983702). RNAseq showed that the c.1639-6T>A variant leads to the use of a cryptic splice acceptor site in intron 18 that results in the retention of 4 bps of intronic DNA in exon 19 after splicing which leads to a frameshift (p.Gly547AlafsX24; PMID:36983702). The ACMG classification criteria are: PM2 moderate, PM3 moderate, PP1 supporting, PP4 moderate, and PS3 strong. Based on the above data, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003463720	SCV004196509	pathogenic	Miyoshi muscular dystrophy 1	2023-06-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000597734	SCV000789344	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2017-02-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000597734	SCV002079819	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-12-01	no assertion criteria provided	clinical testing