Submissions for variant NM_001079802.2(FKTN):c.1167dup (p.Phe390fs)

dbSNP: rs398123555

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000079427	SCV000329807	pathogenic	not provided	2024-04-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 72 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Reported in association with Fukuyama congenital muscular dystrophy (FCMD), limb girdle muscular dystrophy (LGMD), and Walker-Warburg syndrome (WWS) (PMID: 17044012, 10545611, 18177472, 18752264, 19266496); Reported with a second variant in the FKTN gene in a patient with dilated cardiomyopathy; however, segregation information was not provided (PMID: 32746448); Founder mutation in the Ashkenazi Jewish population, present in 81/10350 (0.78%) alleles from individuals of Ashkenazi Jewish ancestry in large population cohorts (gnomAD; PMID: 18177472, 19266496, 18752264); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 3203; ClinVar); This variant is associated with the following publications: (PMID: 18752264, 18177472, 19266496, 20961758, 10545611, 27065010, 29327352, 31980526, 32746448, 17044012)
Eurofins Ntd Llc (ga)	RCV000079427	SCV000331176	pathogenic	not provided	2012-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003356	SCV000698716	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	2016-01-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000634081	SCV000755359	pathogenic	Walker-Warburg congenital muscular dystrophy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe390Ilefs*14) in the FKTN 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 FKTN protein. This variant is present in population databases (rs756763804, gnomAD 0.8%). This premature translational stop signal has been observed in individual(s) with dystroglycanopathies (PMID: 17878207, 18177472, 18752264, 19266496, 27065010). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3203). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000778871	SCV000915268	pathogenic	FKTN-related disorder	2018-11-13	criteria provided, single submitter	clinical testing	The FKTN c.1167dupA (p.Phe390IlefsTer14) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the literature, the p.Phe390IlefsTer14 variant has been reported in at least 13 individuals, four of whom are related, diagnosed with a range of conditions. The p.Phe390IlefsTer14 variant was reported to occur de novo in a Japanese individual with a severe Fukuyama congenital muscular dystrophy (FCMD), who also carried the common 3 kb retrotransposal insertion allele in the FKTN gene (Kondo-lida et al. 1999). The variant has also been reported also reported in a compound heterozygous state in three individuals presenting with a limb girdle muscular dystrophy with no intellectual disability or brain abnormalities; two of the individuals are related and carry the variant in trans with a missense variant while the third carried the variant in trans with a second frameshift variant (Godfrey et al. 2006). Additionally the p.Phe390IlefsTer14 variant has been reported in a homozygous state in nine individuals with Walker-Warburg syndrome, a more severe phenotype, all of whom are of Ashkenazi Jewish ancestry from non-consanguineous families and share a common haplotype. The variant was detected in two or 299 alleles in a healthy American Ashkenazi Jewish control population suggesting this may be a founder variant in this population (Cotarelo et al. 2008; Manzini et al. 2008; Chang et al. 2009). The p.Phe390IlefsTer14 variant is reported at a frequency of 0.007991 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence and potential impact of frameshift variants, the p.Phe390IlefsTer14 variant is classified as pathogenic for FKTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000003356	SCV001163214	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000003356	SCV001193928	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	2019-11-15	criteria provided, single submitter	clinical testing	NM_001079802.1(FKTN):c.1167dupA(F390Ifs*14) is classified as pathogenic in the context of FKTN-related disorders. Sources cited for classification include the following: PMID 19266496, 18752264, 17878207, 10545611, 18177472 and 24144914. Classification of NM_001079802.1(FKTN):c.1167dupA(F390Ifs*14) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000003357	SCV001448834	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2M	2019-03-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000079427	SCV002023727	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326661	SCV002629460	pathogenic	Cardiovascular phenotype	2022-08-24	criteria provided, single submitter	clinical testing	The c.1167dupA pathogenic mutation, located in coding exon 8 of the FKTN gene, results from a duplication of A at nucleotide position 1167, causing a translational frameshift with a predicted alternate stop codon (p.F390Ifs*14). This alteration occurs at the 3' terminus of theFKTN gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 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 mutation has been detected in both the compound heterozygous and homozygous states in individuals with Fukuyama congenital muscular dystrophy (FCMD) and Walker-Warburg syndrome (WWS). In addition, this mutation is present in 0.8% of healthy Ashkenazi Jewish individuals, and often occurs on one specific haplotype, suggesting it may be a founder mutation in this population (Kondo-Iida E et al. Hum. Mol. Genet., 1999 Nov;8:2303-9; Chang W et al. Prenat. Diagn., 2009 Jun;29:560-9; Cotarelo RP et al. Clin. Genet., 2008 Feb;73:139-45; Godfrey C et al. Ann. Neurol., 2006 Nov;60:603-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003356	SCV002767381	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type 4A (MIM#253800). (I) 0106 - This gene is associated with autosomal recessive disease. Recessive pathogenic variants in this gene can cause three types of muscular dystrophy-dystroglycanopathy: a severe congenital form with brain and eye anomalies (type A4; MIM# 253800), formerly designated Fukuyama congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), or muscle-eye-brain disease (MEB), a less severe congenital form without impaired intellectual development (type B4; MIM# 613152), and a milder limb-girdle form (type C4; MIM# 611588). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (97 heterozygotes, 0 homozygotes) and is enriched in the Ashkenazi Jewish population. (SP) 0604 - Variant is not predicted to truncate an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. At least three downstream truncating variants have previously been classified as pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in many individuals with muscular dystrophy-dystroglycanopathies and is considered to be a founder variant in the Ashkenazi Jewish population. When homozygous, the variant results in the severe congenital type 4A form of disease with brain and eye anomalies (MIM#253800), however the type can vary when in compound heterozygosity with a different variant (ClinVar, LOVD, PMID: 19266496). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002476917	SCV002776954	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	2022-03-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466792	SCV004199715	pathogenic	Dilated cardiomyopathy 1X	2024-03-21	criteria provided, single submitter	clinical testing
OMIM	RCV000003356	SCV000023514	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	2008-02-01	no assertion criteria provided	literature only
OMIM	RCV000003357	SCV000023515	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2M	2008-02-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000634081	SCV002081970	pathogenic	Walker-Warburg congenital muscular dystrophy	2020-04-03	no assertion criteria provided	clinical testing