Submissions for variant NM_001130987.2(DYSF):c.4911G>A (p.Lys1637=)

dbSNP: rs141704244

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000387010	SCV000342093	uncertain significance	not provided	2016-05-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241552	SCV001414578	pathogenic	Qualitative or quantitative defects of dysferlin	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change affects codon 1598 of the DYSF mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DYSF protein. This variant also falls at the last nucleotide of exon 43, which is part of the consensus splice site for this exon. This variant is present in population databases (rs141704244, gnomAD 0.05%). This variant has been observed in individual(s) with limb-girdle muscular dystrophy (Invitae). 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: 288089). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.4794G nucleotide in the DYSF gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 27195159). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001828247	SCV004047096	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B		criteria provided, single submitter	clinical testing	The synonymous variant p.K1637= in DYSF (NM_001130987.2) has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. This p.Lys1637 type of mutation causes no change in the protein that is produced, which is why it's considered as synonymous mutation. This variant also falls at the last nucleotide of exon 43 of the DYSF coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (Buratti et al, 2007, Zhang et al, 1998). The nucleotide c.4911 in DYSF is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. In the absence of another reportable variant molecular diagnosis is not confirmed.
Molecular Genetics, Royal Melbourne Hospital	RCV001241552	SCV004812300	uncertain significance	Qualitative or quantitative defects of dysferlin	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change is a synonymous (silent) variant altering the last base of exon 44 of DYSF that is predicted to impact splicing (SpliceAI). The highest population minor allele frequency in the population database gnomAD v4.0 is 0.04% (39/91,076 alleles) in the South Asian population, which is consistent with recessive disease. This variant has been observed with a second variant of uncertain significance in an individual with limb-girdle muscular dystrophy (LGMD, PMID: 30564623). Another variant at the same nucleotide position (c.4911G>T) with a similar predicted splice impact to the variant under assessment has been classified as likely pathogenic for LGMD (ClinVar ID: ID: 94331; PMID: 21520333, 27195159, 30564623, 33610434, 36983702). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3, PS1_Moderate.
Breakthrough Genomics, Breakthrough Genomics	RCV000387010	SCV005187736	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001828247	SCV002082348	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2019-10-28	no assertion criteria provided	clinical testing