Submissions for variant NM_001079802.2(FKTN):c.139C>T (p.Arg47Ter)

gnomAD frequency: 0.00001  dbSNP: rs119463990

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594458	SCV000700729	pathogenic	not provided	2017-03-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811518	SCV000951786	pathogenic	Walker-Warburg congenital muscular dystrophy	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg47*) 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 (rs119463990, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Fukuyama-type congenital muscular dystrophy (PMID: 9690476, 19842201; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3200). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003353	SCV001737678	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	2021-06-10	criteria provided, single submitter	clinical testing	Variant summary: FKTN c.139C>T (p.Arg47X) 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 1.6e-05 in 251276 control chromosomes. c.139C>T has been reported in the literature in multiple individuals affected with Fukuyama congenital muscular dystrophy (FCMD) (example, Kobayashi_1998, Vuillaumier-Barrot_2009, Xiong_2009, Yang_2015, Kitamura_2016) and at-least one patient with Walker-Warburg syndrome (WWS) (example, Yis_2011). These data indicate that the variant is very likely to be associated with disease. Two 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.
GeneDx	RCV000594458	SCV001766999	pathogenic	not provided	2019-10-21	criteria provided, single submitter	clinical testing	Reported in conjunction with a second missense variant in the FKTN gene in a 7 year old boy with proximal muscle weakness, calf muscle hypertrophy, post-exercise myalgia, and elevated creatinine kinase levels (Vuillaumier-Barrot et al., 2009); Reported as a presumably de novo variant in a Greek/Croatian female with Walker-Warburg syndrome who also harbored a second maternally inherited FKTN variant, although the authors do not comment on phase of the variants (Yis et al., 2011); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 3200; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 30564623, 9690476, 25814170, 20961758, 19179078, 11165248, 24144914, 23582336, 21191726, 23891399, 25525159, 19842201)
Revvity Omics, Revvity	RCV000594458	SCV002023726	pathogenic	not provided	2019-10-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000594458	SCV002770880	pathogenic	not provided	2021-09-24	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Ambry Genetics	RCV003372594	SCV004085754	pathogenic	Cardiovascular phenotype	2023-08-14	criteria provided, single submitter	clinical testing	The p.R47* pathogenic mutation (also known as c.139C>T), located in coding exon 2 of the FKTN gene, results from a C to T substitution at nucleotide position 139. This changes the amino acid from an arginine to a stop codon within coding exon 2. This variant has co-occurred with other mutations in the FKTN gene in several individuals with muscular dystrophy phenotypes, including in trans co-occurrences (Kobayashi K et al. Nature, 1998 Jul;394:388-92; Matsumoto H et al. Neuromuscul Disord, 2005 May;15:342-8; Vuillaumier-Barrot S et al. Neuromuscul Disord, 2009 Mar;19:182-8; Xiong H et al. Am J Med Genet A, 2009 Nov;149A:2403-8; Kondo H et al. Jpn J Ophthalmol, 2010 Nov;54:622-4; Yis U et al. Neuromuscul Disord, 2011 Jan;21:20-30; Kobayashi K et al. J Hum Genet, 2017 Nov;62:945-948). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV003472962	SCV004199745	pathogenic	Dilated cardiomyopathy 1X	2024-03-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000594458	SCV005413896	pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing	PM2_moderate, PM3, PS4_moderate, PVS1
OMIM	RCV000003353	SCV000023511	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	1998-07-23	no assertion criteria provided	literature only
Natera, Inc.	RCV000811518	SCV002078743	pathogenic	Walker-Warburg congenital muscular dystrophy	2021-03-26	no assertion criteria provided	clinical testing