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

gnomAD frequency: 0.00001  dbSNP: rs104894692

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Counsyl	RCV000004455	SCV000793054	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2017-08-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805125	SCV000945070	pathogenic	Walker-Warburg congenital muscular dystrophy	2024-06-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 307 of the FKRP protein (p.Tyr307Asn). This variant is present in population databases (rs104894692, gnomAD 0.002%). This missense change has been observed in individuals with FKRP-related conditions (PMID: 12666124, 15121789, 16476814, 16634037, 18639457). ClinVar contains an entry for this variant (Variation ID: 4233). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FKRP protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FKRP function (PMID: 19155270, 26923585). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000494504	SCV001250135	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	FKRP: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting
Baylor Genetics	RCV000004454	SCV004197411	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2024-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488324	SCV004241301	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: FKRP c.919T>A (p.Tyr307Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-06 in 158156 control chromosomes. c.919T>A has been reported in the literature in multiple individuals affected with muscle-eye-brain disease, including at-least two homozygous cases (examples, Beltran-Valero de Bernabe_2004, Mercuri_2006). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The homozygote FKRP-Neo mice knocking in the current variant results in a reduction in the laminin-binding epitope of alpha-dystroglycan in muscle, eye and brain, reduced levels of FKRP transcript and a muscle eye brain phenotype mimicking FKRP-related diseases in human (Ackroyd_2009). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publications have been ascertained in the context of this evaluation (PMID: 19155270, 15121789, 16476814). All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004454	SCV000024627	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5	2004-05-01	no assertion criteria provided	literature only
OMIM	RCV000004455	SCV000024628	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2I	2004-05-01	no assertion criteria provided	literature only
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.