ClinVar Miner

Submissions for variant NM_003494.3(DYSF):c.5078G>A (rs779987458)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672247 SCV000797338 likely pathogenic Limb-girdle muscular dystrophy, type 2B 2018-01-23 criteria provided, single submitter clinical testing
Invitae RCV000648020 SCV000769830 uncertain significance Dysferlinopathy 2017-09-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1693 of the DYSF protein (p.Arg1693Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. ]This variant has been reported in the heterozygous state or in combination with another DYSF variant in individuals affected with a dysferlinopathy  (PMID: 16010686, 25868377, 27066573, 18853459). ClinVar contains an entry for this variant (Variation ID: 424774). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg1693Trp) has been determined to be pathogenic (PMID: 16100712, 27066573, 23530687, 27647186, 28403181). This suggests that the arginine residue is critical for DYSF protein function and that other missense substitutions at this position may also be pathogenic. 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.

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