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

Total submissions: 4

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	2019-10-25	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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001197776	SCV001368555	uncertain significance	Polymicrogyria; Abnormality of neuronal migration	2018-10-24	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PS4,PM2,PM4. This variant was detected in heterozygous state.