rs148975262

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001079802.2(FKTN):c.1159G>A(p.Gly387Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,611,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

FKTN
NM_001079802.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:15

Conservation

PhyloP100: 8.89

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy type 2M
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
myopathy caused by variation in FKTN
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy without intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscle-eye-brain disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscular dystrophy-dystroglycanopathy, type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1X
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

FKTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKTN	NM_001079802.2 link	c.1159G>A	p.Gly387Arg	missense_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.1159G>A	p.Gly387Arg	missense_variant	Exon 10 of 11	5	NM_001079802.2	ENSP00000350687.6		O75072-1

Frequencies

GnomAD3 genomes

AF:

0.000476

AC:

AN:

151402

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000870

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000435

AC:

109

AN:

250638

AF XY:

0.000406

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.000837

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000752

AC:

1098

AN:

1459604

Hom.:

Cov.:

AF XY:

0.000728

AC XY:

529

AN XY:

726238

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33414

American (AMR)

AF:

0.000157

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.00

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

53154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000936

AC:

1039

AN:

1110444

Other (OTH)

AF:

0.000531

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000475

AC:

AN:

151520

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

AN XY:

74032

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

41324

American (AMR)

AF:

0.000197

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000870

AC:

AN:

67828

Other (OTH)

AF:

0.00

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000717

Hom.:

Bravo

AF:

0.000427

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000453

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Dec 29, 2023

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function. -

May 19, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with idiopathic ventricular fibrillation (PMID: 37227348); This variant is associated with the following publications: (PMID: 30564623, 37227348) -

Nov 10, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 13, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FKTN c.1159G>A; p.Gly387Arg variant (rs148975262, ClinVar Variation ID: 167070), is reported in the literature in an individuals affected with idiopathic ventricular fibrillation, thought no additional evidence of causality was provided (Pannone 2023). This variant is found in the non-Finnish European population with an allele frequency of 0.08% (106/128,630 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.684). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Pannone L et al. Genetics in Probands With Idiopathic Ventricular Fibrillation: A Multicenter Study. JACC Clin Electrophysiol. 2023 Aug;9(8 Pt 1):1296-1306. PMID: 37227348. -

Cardiovascular phenotype

Uncertain:2

Dec 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G387R variant (also known as c.1159G>A), located in coding exon 8 of the FKTN gene, results from a G to A substitution at nucleotide position 1159. The glycine at codon 387 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in a pediatric cardiomyopathy cohort and a ventricular fibrillation cohort (Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298; Pannone L et al. JACC Clin Electrophysiol, 2023 Aug;9:1296-1306). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3 -

Walker-Warburg congenital muscular dystrophy

Uncertain:2

Apr 03, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 387 of the FKTN protein (p.Gly387Arg). This variant is present in population databases (rs148975262, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FKTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 167070). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

not specified

Uncertain:1

Dec 19, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FKTN c.1159G>A (p.Gly387Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 250638 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FKTN causing Cardiomyopathy (0.00043 vs 0.005), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1159G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (Internal data, MYBPC3, c.3627+1G>A), providing supporting evidence for a benign role. Eight 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

FKTN-related disorder

Uncertain:1

Nov 21, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The FKTN c.1159G>A variant is predicted to result in the amino acid substitution p.Gly387Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.082% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Feb 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1X

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;D;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;.;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

1.3

L;L;L;L

PhyloP100

8.9

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.4

.;D;.;D

REVEL

Pathogenic

0.68

Sift

Benign

0.081

.;T;.;D

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.67

P;P;.;.

Vest4

0.86

MutPred

0.76

Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);

MVP

0.92

MPC

0.47

ClinPred

0.32

GERP RS

6.0

Varity_R

0.41

gMVP

0.85

Mutation Taster

=16/84

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over