Submissions for variant NM_001079802.2(FKTN):c.1270G>A (p.Gly424Ser)

dbSNP: rs752358445

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000267506	SCV000345188	uncertain significance	not provided	2016-09-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459192	SCV000546101	uncertain significance	Walker-Warburg congenital muscular dystrophy	2022-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the FKTN protein (p.Gly424Ser). This variant is present in population databases (rs752358445, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 32969603, 34120883; Invitae). ClinVar contains an entry for this variant (Variation ID: 290602). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222481	SCV002500753	pathogenic	Primary familial dilated cardiomyopathy	2023-05-09	criteria provided, single submitter	clinical testing	Variant summary: FKTN c.1270G>A (p.Gly424Ser) results in a non-conservative amino acid change located in the region involved in the phosphorylation of the C-terminal end (Larranaga-Moreira_2021) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251418 control chromosomes (gnomAD). c.1270G>A has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy and this variant co-segregated with the disease in two unrelated families (example: Larranaga-Moreira_2021, Villarreal-Molina_2020, Winckler_2022). These data indicate that the variant is very likely to be associated with disease. Additionally, a muscle biopsy from the homozygous individual in Larranaga-Moreira_2021 showed severe reduction in alpha-dystroglycan and slight reduction in laminin alpha2 compared with healthy control. The following publications have been ascertained in the context of this evaluation (PMID: 32969603, 34120883, 33048919, 35175440). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003475923	SCV004199750	likely pathogenic	Dilated cardiomyopathy 1X	2023-03-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004619249	SCV005118152	likely pathogenic	Cardiovascular phenotype	2024-03-20	criteria provided, single submitter	clinical testing	The p.G424S variant (also known as c.1270G>A), located in coding exon 9 of the FKTN gene, results from a G to A substitution at nucleotide position 1270. The glycine at codon 424 is replaced by serine, an amino acid with similar properties. This variant has been identified in the homozygous state in individuals with features consistent with limb girdle muscular dystrophy with cardiac-involvement (Larrañaga-Moreira JM et al. Rev Esp Cardiol (Engl Ed), 2021 Nov;74:987-989;Winckler PB et al. Neurol Sci, 2022 Jul;43:4473-4481). This variant has also been identified in the homozygous state in two siblings with severe dilated cardiomyopathy not known to have features of skeletal muscle involvement (Villarreal-mMolina MT et al. Rev Invest Clin, 2020 May;73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic.