9-105620049-GAAA-GAAAA

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001079802.2(FKTN):c.1167dupA(p.Phe390IlefsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,611,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

FKTN
NM_001079802.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 2.53

Variant links:

Genes affected

FKTN (HGNC:3622): (fukutin) The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]

FKTN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-105620049-G-GA is Pathogenic according to our data. Variant chr9-105620049-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 3203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKTN	NM_001079802.2 link	c.1167dupA	p.Phe390IlefsTer14	frameshift_variant	Exon 10 of 11	ENST00000357998.10	NP_001073270.1	O75072-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10 link	c.1167dupA	p.Phe390IlefsTer14	frameshift_variant	Exon 10 of 11	5	NM_001079802.2	ENSP00000350687.6		O75072-1

Frequencies

GnomAD3 genomes

AF:

0.000165

AC:

AN:

151640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000367

AC:

AN:

250506

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

135522

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00765

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000186

AC:

271

AN:

1459616

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

726236

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00720

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.000514

GnomAD4 genome

AF:

0.000165

AC:

AN:

151640

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74042

show subpopulations

Gnomad4 AFR

AF:

0.0000485

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.000170

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4

Pathogenic:5

Feb 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 18, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

not provided

Pathogenic:3

Dec 06, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 39399040, 18177472, 19266496, 20961758, 10545611, 27065010, 29327352, 31980526, 17044012, 32746448, 38361118) -

Sep 12, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2M

Pathogenic:2

Mar 21, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Walker-Warburg congenital muscular dystrophy

Pathogenic:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 03, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

FKTN-related disorder

Pathogenic:1

Nov 13, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4;C1969040:Autosomal recessive limb-girdle muscular dystrophy type 2M;C2751052:Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

Pathogenic:1

Apr 25, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4;C1969024:Dilated cardiomyopathy 1X;C1969040:Autosomal recessive limb-girdle muscular dystrophy type 2M;C2751052:Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4

Pathogenic:1

Jan 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1X

Pathogenic:1

Mar 21, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Aug 24, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over