ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.1270A>C (p.Asn424His) (rs769568971)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726824 SCV000618022 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FKRP gene. The N424H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N424H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The N424H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726824 SCV000703316 uncertain significance not provided 2016-12-14 criteria provided, single submitter clinical testing
Invitae RCV000634052 SCV000755330 uncertain significance Walker-Warburg congenital muscular dystrophy 2017-09-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 424 of the FKRP protein (p.Asn424His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs769568971, ExAC 0.008%). This variant has not been reported in the literature in individuals with FKRP-related disease. 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.

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