ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.1269_1270insT (p.Asn424Ter)

gnomAD frequency: 0.00001  dbSNP: rs772950604
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000382228 SCV000343378 pathogenic not provided 2016-07-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001386555 SCV001586817 pathogenic Walker-Warburg congenital muscular dystrophy 2023-05-12 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FKRP protein in which other variant(s) (p.Ile478Thr) have been determined to be pathogenic (PMID: 16476814, 18639457, 19299310). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 289093). This variant has not been reported in the literature in individuals affected with FKRP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn424*) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 72 amino acid(s) of the FKRP protein.
Ambry Genetics RCV003278742 SCV004003022 pathogenic Cardiovascular phenotype 2023-05-25 criteria provided, single submitter clinical testing The c.1269_1270insT pathogenic mutation, located in coding exon 1 of the FKRP gene, results from an insertion of one nucleotide at position 1269, causing a translational frameshift with a predicted alternate stop codon (p.N424*). This alteration occurs at the 3' terminus of theFKRP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 72 amino acids (~15%) of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics RCV003463774 SCV004197452 likely pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 2022-05-11 criteria provided, single submitter clinical testing

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