Submissions for variant NM_001130987.2(DYSF):c.4911G>T (p.Lys1637Asn)

dbSNP: rs141704244

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000080297	SCV000333448	uncertain significance	not provided	2015-08-04	criteria provided, single submitter	clinical testing
Invitae	RCV000548178	SCV000649707	pathogenic	Qualitative or quantitative defects of dysferlin	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1598 of the DYSF protein (p.Lys1598Asn). 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 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 21520333, 27195159, 30564623, 33610434, 36983702). 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: 94331). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 36983702). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222381	SCV002500427	uncertain significance	not specified	2022-03-16	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.4794G>T (p.Lys1598Asn) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251434 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (6e-05 vs 0.0031), allowing no conclusion about variant significance. c.4794G>T has been reported in the literature in individuals affected with dysferlinopathy, including limb-girdle muscular dystrophy and Miyoshi myopathy (Harris_2016, Swaika_2016, Nallamilli_2018, Klee_2021, Moore_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000080297	SCV003831326	likely pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing
Jain Foundation	RCV000548178	SCV003935029	likely pathogenic	Qualitative or quantitative defects of dysferlin	2023-03-13	criteria provided, single submitter	research	This variant is rare with an allele frequency in gnomad of 0.0054%. This variant has been observed in individuals with dysferilnopathy (PMID: 36983702, 21520333, 27195159, 30564623). In the majority of the cases, this variant is seen in the heterozygous state in conjunction with another likely pathogenic or pathogenic DYSF variant and in one case it has been shown to be in trans with the pathogenic DYSF variant, Arg1586X (PMID: 21520333). RNAseq analysis showed that this variant causes a leaky splice site that leads to 26-30% of all transcripts and 60% of the allele with this variant having an inframe deletion of exon 43 (p.G1547_K1598del), which deletes part of C2F which leads to the loss of 6% of the dysferlin protein amino acid sequence (PMID: 36983702). The remaining 40% of the allele with this variant results in the replacement of lysine with asparagine (p.K1598N). The ACMG classification criteria are: PM2 moderate, PM3 strong, PM4 moderate, PP4 supporting. Based on the above data, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003466986	SCV004194170	likely pathogenic	Miyoshi muscular dystrophy 1	2023-10-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001271548	SCV001452783	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV004549503	SCV002075093	not provided	DYSF-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.