Submissions for variant NM_001079802.2(FKTN):c.1371_1381dup (p.Tyr461fs)

dbSNP: rs727502847

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000149977	SCV000196833	pathogenic	not provided	2015-03-23	criteria provided, single submitter	clinical testing	c.1371_1381dupTATCCAGTTAT: p.Tyr461LeufsX10 in exon 11 in the FKTN gene (NM_001079802.1). The normal sequence with the bases that are duplicated in braces is: TTAT{insTATCCAGTTAT}ATTG. The c.1371_1381dupTATCCAGTTAT pathogenic variant in the FKTN gene has not been reported previously as a disease-causing pathogenic variant nor as a benign polymorphism, to our knowledge. The c.1371_1381dupTATCCAGTTAT pathogenic variant causes a frameshift starting with codon Tyrosine 461, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Tyr461LeufsX10. The c.1371_1381dupTATCCAGTTAT pathogenic variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other frameshift pathogenic variants have been reported in association with FKTN-related muscular dystrophies. We interpret c.1371_1381dupTATCCAGTTAT as a disease-causing pathogenic variant. The variant is found in FKTN panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791654	SCV000930913	uncertain significance	Walker-Warburg congenital muscular dystrophy	2022-02-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr461Leufs*10) in the FKTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1 amino acid(s) of the FKTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with abnormality of the cardiovascular system (PMID: 26633542). ClinVar contains an entry for this variant (Variation ID: 162569). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Genetics and Genomics Program, Sidra Medicine	RCV001293213	SCV001434211	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research