ClinVar Miner

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

dbSNP: rs752358445
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Total submissions: 4
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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
Invitae 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

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