Submissions for variant NM_001130987.2(DYSF):c.1258del (p.Ala420fs)

dbSNP: rs779969348

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001382718	SCV001581620	pathogenic	Qualitative or quantitative defects of dysferlin	2023-09-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1070532). This premature translational stop signal has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (Invitae). This variant is present in population databases (rs779969348, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Ala388Profs*11) 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).
CeGaT Center for Human Genetics Tuebingen	RCV001726541	SCV001962263	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001382718	SCV003922177	pathogenic	Qualitative or quantitative defects of dysferlin	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Ala420ProfsTer11 variant in DYSF was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 242418), in one individual with limb-girdle muscular dystrophy (PMID: 32528171). Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 242418). The p.Ala420ProfsTer11 variant in DYSF has not been previously reported in individuals with limb-girdle muscular dystrophy 2 but has been identified in 0.009% (3/34582) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs527435707). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1070532) and has been interpreted as pathogenic by Invitae and the CeGaT Center for Human Genetics Tuebingen. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 420 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the DYSF gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy 2. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive limb-girdle muscular dystrophy 2. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015).
Baylor Genetics	RCV003469680	SCV004192249	pathogenic	Miyoshi muscular dystrophy 1	2023-02-23	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004555622	SCV005044806	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B		criteria provided, single submitter	clinical testing	The frameshift c.1258del p.Ala420ProfsTer11 variant in DYSF gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala420ProfsTer11 variant is reported with allele frequency of 0.002% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Alanine 420, changes this amino acid to Proline residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Ala420ProfsTer11. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.