Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000587372 | SCV000698718 | pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 | 2023-01-24 | criteria provided, single submitter | clinical testing | Variant summary: FKTN c.648-1243G>T involves the alteration of a non-conserved nucleotide resulting in an intronic change. Several computational tools predict a significant impact on normal splicing: Two predict the variant strengthens a cryptic 5' donor site. One predicts the variant creates a cryptic 5' donor site. In addition, this variant is predicted to create a pseudoexon between exon 5 and exon 6 resulting in a frameshift and a premature stop codon (Kobayashi_2017). Another study showed patients with parental origins of this variant and direct sequencing of RNA showed the 64bp pseudogene insertion (Lim_2010). The variant was absent in 192 control chromosomes (gnomAD and publication data). c.648-1243G>T has been reported in the literature as a compound heterozygous genotype with a pathogenic variant in multiple individuals affected with Fukuyama Congenital Muscular Dystrophy (Example: Suzuki_2022, Kobayashi_2017, Lim_2010 etc.) and was shown to segregate with disease (Kobayashi_2017). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite this variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV000763612 | SCV000894463 | likely pathogenic | Dilated cardiomyopathy 1X; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4; Autosomal recessive limb-girdle muscular dystrophy type 2M; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1; Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001217950 | SCV001389813 | pathogenic | Walker-Warburg congenital muscular dystrophy | 2023-11-14 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 6 of the FKTN gene. It does not directly change the encoded amino acid sequence of the FKTN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with congenital muscular dystrophy (PMID: 20620061, 28680109). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.647+2084G>T. ClinVar contains an entry for this variant (Variation ID: 496331). Studies have shown that this variant results in insertion of a pseudoexon and introduces a premature termination codon (PMID: 20620061, 28680109). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV003471945 | SCV004199719 | pathogenic | Dilated cardiomyopathy 1X | 2024-03-24 | criteria provided, single submitter | clinical testing |