rs375366821
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM5PP2PP3_ModerateBS2
The NM_001458.5(FLNC):c.4219G>A(p.Val1407Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,842 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1407?) has been classified as Pathogenic.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.4219G>A | p.Val1407Met | missense_variant | 24/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.4219G>A | p.Val1407Met | missense_variant | 24/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.4219G>A | p.Val1407Met | missense_variant | 24/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.4219G>A | p.Val1407Met | missense_variant | 24/47 | 1 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249510Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135378
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461842Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727228
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2022 | The p.V1407M variant (also known as c.4219G>A), located in coding exon 24 of the FLNC gene, results from a G to A substitution at nucleotide position 4219. The valine at codon 1407 is replaced by methionine, an amino acid with highly similar properties. 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1407 of the FLNC protein (p.Val1407Met). This variant is present in population databases (rs375366821, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 571297). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at