Submissions for variant NM_001130987.2(DYSF):c.4597T>C (p.Tyr1533His) (rs150139276)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	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	uncertain significance	Dysferlinopathy	2018-08-02	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with histidine at codon 1494 of the DYSF protein (p.Tyr1494His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs150139276, ExAC 0.07%). This variant has been reported in an individual affected with limb-girdle muscular dystrophy or Miyoshi myopathy (PMID: 21522182). However, in that individual, a pathogenic allele as well as a second rare variant were also identified in DYSF, and it is unknown if these variants are on the same or opposite chromosome as this p.Tyr1494His change. ClinVar contains an entry for this variant (Variation ID: 285356) Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000664797	SCV000788812	uncertain significance	Limb-girdle muscular dystrophy, type 2B	2016-12-16	criteria provided, single submitter	clinical testing

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