Submissions for variant NM_001130987.2(DYSF):c.4597T>C (p.Tyr1533His)

gnomAD frequency: 0.00034  dbSNP: rs150139276

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725642	SCV000338340	uncertain significance	not provided	2017-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000725642	SCV000589641	uncertain significance	not provided	2018-09-14	criteria provided, single submitter	clinical testing	The Y1494H variant in the DYSF gene has been reported previously in an individual with a limb-girdle muscular dystrophy or a Miyoshi myopathy diagnosis, and 5% dysferlin mRNA on muscle biopsy, who was also heterozygous for two additional DYSF variants; however segregation information was not reported (Cacciottolo et al., 2011). The Y1494H variant is observed in 34/51252 (0.066%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The Y1494H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Y1494H as a variant of uncertain significance.
Invitae	RCV000530924	SCV000649697	likely benign	Qualitative or quantitative defects of dysferlin	2024-01-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000664797	SCV000788812	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2016-12-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000530924	SCV001298020	uncertain significance	Qualitative or quantitative defects of dysferlin	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000725642	SCV002541836	uncertain significance	not provided	2021-12-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725642	SCV003829645	uncertain significance	not provided	2022-06-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235177	SCV003933721	uncertain significance	not specified	2023-05-05	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.4480T>C (p.Tyr1494His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 247334 control chromosomes in the gnomAD database, including 1 homozygote (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00044 vs 0.0031), allowing no conclusion about variant significance. c.4480T>C has been reported in the literature in at least one individual affected with Limb-Girdle Muscular Dystrophy, however without strong evidence for causality (e.g., Cacciottolo_2011). This report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21522182, 25898921). Eight ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments, with 7 submitters classifying the variant as uncertain significance and one submitter classifying it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000664797	SCV002082333	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-01-24	no assertion criteria provided	clinical testing