ClinVar Miner

Submissions for variant NM_006731.2(FKTN):c.869A>T (p.Lys290Ile) (rs755092516)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255453 SCV000321646 uncertain significance not provided 2017-11-24 criteria provided, single submitter clinical testing The K290I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The K290I variant is observed in 67/34,420 (0.2%) alleles from individuals of Latino background (Lek et al., 2016). The K290I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000459614 SCV000546098 uncertain significance Walker-Warburg congenital muscular dystrophy 2018-05-31 criteria provided, single submitter clinical testing This sequence change replaces lysine with isoleucine at codon 290 of the FKTN protein (p.Lys290Ile). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and isoleucine. This variant is present in population databases (rs755092516, ExAC 0.2%). This variant has not been reported in the literature in individuals with FKTN-related disease. ClinVar contains an entry for this variant (Variation ID: 265152). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000255453 SCV000924798 uncertain significance not provided 2017-06-12 no assertion criteria provided provider interpretation p.Lys290Ile (c.869A>T) in the FKTN gene (NM_001079802.1) GeneDx classifies this variant as a variant of uncertain significance. Given its prevalence in the general population we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). In addition, two pathogenic variants in the FKTN gene must be present for an individual to manifest symptoms. The FKTN gene encodes the fukutin protein, in which two loss of function variants (autosomal recessive inheritance) causes a severe muscular dystrophy. Autosomal recessive inheritance of both loss-of-function and pathogenic missense variants can cause a severe dilated cardiomyopathy that tends to onset in childhood. In a paper by Arimura et al (2009), 1 out of 172 DCM patients was a compound heterozygote for a deletion and missense variant (p.Cys101Phe in the FKTN gene. This was a 19 year old Japanese patient with a high CK and symptoms of DCM, accompanied by a reduced ejection fraction. Two other DCM patients and 3 controls were heterozygous for the insertion allele demonstrating that a single pathogenic variant is not enough to cause severe disease. Murakami et al (2006) identified compound heterozygous pathogenic variants in 6 individuals from 4 families with dilated cardiomyopathy and no signs of muscular dystrophy: one patient died at 12 years old and another required transplant at 18. There is no published literature to indicate that this variant is associated with cardiomyopathy. There is no published literature showing that a single variant predisposes an individual to cardiovascular disease. This variant is present in ClinVar. It has been submitted by two labs: GeneDx and Invitae, both of which classify this variant as a variant of uncertain significnace. Invitae saw this variant in a patient with Walker-Warburg congential muscular dystrophy. Per the test report, "in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function". The lysine at codon 290 is not conserved across species, nor are neighboring amino acids. There are few variants at nearby codons listed in ClinVar. The variant was reported online in 68 of 138,611 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 67 of 17,210 individuals of Latino descent (MAF=0.2%) and 1 of 3,234 individuals of "other" descent. Another variant at this codon, p.Lys290Glu is present in 1 out of 123,125 individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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