Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001079802.2(FKTN):c.920G>A(p.Arg307Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,584,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R307G) has been classified as Likely pathogenic.
FKTN (HGNC:3622): (fukutin) The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]
Verdict is Pathogenic. Variant got 16 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
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PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr9-105617967-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 528827.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
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PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.963
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 9-105617968-G-A is Pathogenic according to our data. Variant chr9-105617968-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-105617968-G-A is described in Lovd as [Pathogenic]. Variant chr9-105617968-G-A is described in Lovd as [Likely_pathogenic]. Variant chr9-105617968-G-A is described in Lovd as [Likely_pathogenic]. Variant chr9-105617968-G-A is described in Lovd as [Pathogenic].
Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4 Pathogenic:1
Pathogenic, no assertion criteria provided
literature only
OMIM
May 26, 2009
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Dilated cardiomyopathy 1X Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
May 05, 2023
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not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Jun 15, 2017
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Autosomal recessive limb-girdle muscular dystrophy type 2M Pathogenic:1
Pathogenic, no assertion criteria provided
literature only
OMIM
May 26, 2009
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
May 02, 2019
Variant summary: FKTN c.920G>A (p.Arg307Gln) results in a conservative amino acid change in 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 1.2e-05 in 249118 control chromosomes (gnomAD). c.920G>A has been reported in the literature in multiple affected individuals (Ceyhan-Birsoy_2015, Godfrey_2007, Johnson_2018, Yis_2011). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 307 of the FKTN protein (p.Arg307Gln). This variant is present in population databases (rs119463992, gnomAD 0.01%). This missense change has been observed in individual(s) with FKTN-related conditions (PMID: 17044012, 19179078, 19396839, 25821721, 30060766). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3208). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FKTN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FKTN function (PMID: 26923585). For these reasons, this variant has been classified as Pathogenic. -