Submissions for variant NM_001079802.2(FKTN):c.166-4A>G

gnomAD frequency: 0.00125  dbSNP: rs193922689

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844018	SCV000052457	uncertain significance	not specified	2022-02-28	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000710133	SCV000196829	likely benign	not provided	2021-02-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28798025)
Eurofins Ntd Llc (ga)	RCV000710133	SCV000334290	uncertain significance	not provided	2017-11-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000405586	SCV000476413	uncertain significance	Dilated cardiomyopathy 1X	2018-01-13	criteria provided, single submitter	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.
Illumina Laboratory Services, Illumina	RCV000311406	SCV000476414	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	2018-01-13	criteria provided, single submitter	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.
Athena Diagnostics	RCV000710133	SCV000613315	uncertain significance	not provided	2017-09-22	criteria provided, single submitter	clinical testing
Invitae	RCV001086528	SCV000630817	benign	Walker-Warburg congenital muscular dystrophy	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710133	SCV001155699	uncertain significance	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000710133	SCV001716026	uncertain significance	not provided	2021-06-03	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470721	SCV002769369	uncertain significance	Myopathy caused by variation in FKTN	2020-10-19	criteria provided, single submitter	clinical testing	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
PreventionGenetics, part of Exact Sciences	RCV004541024	SCV004766041	likely benign	FKTN-related disorder	2023-11-30	criteria provided, single submitter	clinical testing	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).
Ambry Genetics	RCV004018687	SCV004871082	uncertain significance	Cardiovascular phenotype	2022-06-02	criteria provided, single submitter	clinical testing	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.