ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.919T>A (p.Tyr307Asn) (rs104894692)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000004455 SCV000793054 likely pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C5 2017-08-02 criteria provided, single submitter clinical testing
GeneDx RCV000494504 SCV000582738 likely pathogenic not provided 2016-04-19 criteria provided, single submitter clinical testing The Y307N variant in the FKRP gene has previously been reported in the homozygous state, as well as the compound heterozygous state, in association with FKRP-related disorders (Mercuri et al., 2003; Beltran-Valero de Bernabe et al., 2004; Sveen et al., 2006). In addition, missense variants in nearby residues (P305S, Y309C, R312C) have been reported in the Human Gene Mutation Database in association with FKRP-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The Y307N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. Additionally, the Y307N variant was not observed in approximately 5,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, the Y307N variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
GenomeConnect, ClinGen RCV000844942 SCV000986760 not provided FKRP-Related Disorder no assertion provided phenotyping only Variant interpretted as Likely pathogenic and reported on 05/09/2016 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000805125 SCV000945070 pathogenic Walker-Warburg congenital muscular dystrophy 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 307 of the FKRP protein (p.Tyr307Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs104894692, ExAC 0.02%). This variant has been observed in several individuals and families affected with FKRP-related conditions (PMID: 12666124, 15121789, 16634037, 16476814, 18639457). ClinVar contains an entry for this variant (Variation ID: 4233). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 26923585, 19155270). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004454 SCV000024627 pathogenic Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A5 2004-05-01 no assertion criteria provided literature only
OMIM RCV000004455 SCV000024628 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C5 2004-05-01 no assertion criteria provided literature only

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