NM_001458.5:c.3799C>T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_001458.5(FLNC):c.3799C>T(p.Arg1267Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000521 in 1,613,554 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1267Q) has been classified as Likely benign.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.3799C>T | p.Arg1267Trp | missense_variant | Exon 22 of 48 | 1 | NM_001458.5 | ENSP00000327145.8 | ||
FLNC | ENST00000346177.6 | c.3799C>T | p.Arg1267Trp | missense_variant | Exon 22 of 47 | 1 | ENSP00000344002.6 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248592Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135144
GnomAD4 exome AF: 0.0000527 AC: 77AN: 1461454Hom.: 0 Cov.: 34 AF XY: 0.0000550 AC XY: 40AN XY: 727030
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74296
ClinVar
Submissions by phenotype
not provided Uncertain:4
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Reported previously in a cohort of healthy controls in a study of individuals with hypertrophic cardiomyopathy (Gomez et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28356264) -
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.R1267W variant (also known as c.3799C>T), located in coding exon 22 of the FLNC gene, results from a C to T substitution at nucleotide position 3799. The arginine at codon 1267 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a healthy control population in a hypertrophic cardiomyopathy study (Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10:[ePub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at