Submissions for variant NM_001079802.2(FKTN):c.642dup (p.Asp215Ter)

dbSNP: rs398123557

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169031	SCV000220181	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	2014-03-22	criteria provided, single submitter	literature only
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000079438	SCV000281461	pathogenic	not provided	2015-01-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000079438	SCV000331086	pathogenic	not provided	2012-12-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000079438	SCV000491171	pathogenic	not provided	2023-01-16	criteria provided, single submitter	clinical testing	Observed in a patient with early-life epilepsy and structural brain malformation; zygosity was not explicitly stated (Berg et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22958903, 23757202, 28759667)
Invitae	RCV000472307	SCV000546097	pathogenic	Walker-Warburg congenital muscular dystrophy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp215*) in the FKTN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKTN are known to be pathogenic (PMID: 17044012, 17878207, 18752264). This variant is present in population databases (rs766898395, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with Walker-Warburg syndrome (PMID: 17878207, 22958903). ClinVar contains an entry for this variant (Variation ID: 93523). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169031	SCV001437307	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	2020-09-21	criteria provided, single submitter	clinical testing	Variant summary: FKTN c.642dupT (p.Asp215X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00014 in 250372 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FKTN causing Walker-Warburg Syndrome (0.00014 vs 0.00046). c.642dupT has been reported in the literature in individuals affected with Walker-Warburg Syndrome (Manzini_2012, Berg_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000079438	SCV002017782	likely pathogenic	not provided	2021-09-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490691	SCV002809170	pathogenic	Dilated cardiomyopathy 1X; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4; Autosomal recessive limb-girdle muscular dystrophy type 2M; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1; Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4	2021-10-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162509	SCV003912553	pathogenic	Cardiovascular phenotype	2022-12-09	criteria provided, single submitter	clinical testing	The c.642dupT pathogenic mutation, located in coding exon 4 of the FKTN gene, results from a duplication of T at nucleotide position 642, causing a translational frameshift with a predicted alternate stop codon (p.D215*). This variant has been detected in the homozygous state in an individual with Walker-Warburg syndrome and was also detected in an individual with early-onset epilepsy and brain malformation for whom zygosity detail was not provided (Manzini MC et al. Am J Hum Genet, 2012 Sep;91:541-7; Berg AT et al. JAMA Pediatr, 2017 Sep;171:863-871). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003474679	SCV004199721	pathogenic	Dilated cardiomyopathy 1X	2023-09-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000472307	SCV002079589	pathogenic	Walker-Warburg congenital muscular dystrophy	2020-05-27	no assertion criteria provided	clinical testing