ClinVar Miner

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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