Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2
The NM_001079802.2(FKTN):c.166-4A>G variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00084 in 1,553,096 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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]
Verdict is Likely_benign. Variant got -4 ACMG points.
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 9-105601141-A-G is Benign according to our data. Variant chr9-105601141-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36139.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Benign=1, Likely_benign=2}.
BS2
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BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Uncertain significance, criteria provided, single submitter
clinical testing
Athena Diagnostics
Sep 22, 2017
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Uncertain significance, criteria provided, single submitter
clinical testing
Mayo Clinic Laboratories, Mayo Clinic
Jun 03, 2021
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Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Nov 17, 2017
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Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Feb 20, 2021
This variant is associated with the following publications: (PMID: 28798025) -
Uncertain significance, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Feb 01, 2019
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not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Feb 28, 2022
Variant summary: FKTN c.166-4A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3 prime acceptor site; one predict the variant weakens a 3 prime acceptor site; three predict the variant creates a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00076 in 243196 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FKTN causing Cardiomyopathy (0.00076 vs 0.005), allowing no conclusion about variant significance. c.166-4A>G has been reported in the literature in individuals affected with Cardiomyopathy. This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/likely benign n=2, VUS n=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Myopathy caused by variation in FKTN Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Oct 19, 2020
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy type A (MIM#253800), type B (MIM#613152), type C (MIM#611588), and dilated cardiomyopathy (MIM#611615) (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (260 heterozygotes, 2 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0705 - No comparable non-canonical splice variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has one benign and five VUS entries in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Dilated cardiomyopathy 1X Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 13, 2018
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. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jun 02, 2022
The c.166-4A>G intronic alteration consists of a A to G substitution 4 nucleotides before coding exon 3 in the FKTN gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 13, 2018
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. -
FKTN-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Nov 30, 2023
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -