ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.4307G>A (p.Gly1436Asp) (rs398123787)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000080287 SCV000613210 pathogenic not provided 2015-12-01 criteria provided, single submitter clinical testing
Center for Genetic Medicine Research,Children's National Medical Center RCV000177998 SCV000265778 likely pathogenic Limb-girdle muscular dystrophy, type 2B 2015-12-01 criteria provided, single submitter research
Counsyl RCV000177998 SCV000795301 likely pathogenic Limb-girdle muscular dystrophy, type 2B 2017-11-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080287 SCV000331195 pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000080287 SCV000589325 pathogenic not provided 2017-09-26 criteria provided, single submitter clinical testing The G1418D pathogenic variant in the DYSF gene has been previously reported, in both the homozygous and compound heterozygous state, in multiple individuals with DYSF-related disorders who had decreased or absent dysferlin expression (Rosas-Vargas et al., 2007; Kesari et al., 2008; Nagaraju et al., 2008; Ankala et al., 2014).The G1418D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret G1418D as a pathogenic variant.
Invitae RCV000536105 SCV000649686 likely pathogenic Dysferlinopathy 2018-05-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 1418 of the DYSF protein (p.Gly1418Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. The frequency data for this variant (rs398123787) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported to segregate with limb-girdle muscular dystrophy type 2B (LGMD2B) in a single family (PMID: 18294055). Additionally, this variant has been reported in the homozygous state or in combination with a second pathogenic variant in unrelated individuals affected with LGMD2B (PMID: 24488599, 18276788, Invitae). ClinVar contains an entry for this variant (Variation ID: 94321). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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