rs1114167361
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong
The NM_001458.5(FLNC):c.3557C>T(p.Ala1186Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,446 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1186A) has been classified as Likely benign.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.3557C>T | p.Ala1186Val | missense_variant | 21/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.3557C>T | p.Ala1186Val | missense_variant | 21/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.3557C>T | p.Ala1186Val | missense_variant | 21/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.3557C>T | p.Ala1186Val | missense_variant | 21/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461446Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727048
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 26 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre | - | The patient was diagnosed with restrictive cardiomyopathy at the age of 3 diagnosed due to atrial enlargement. Mild signs of myopathy and neuropathy including muscle hypotonia were observed and confirmed by electromyography. The parents refused the genetic screening, and so de novo character of mutation was not confirmed. Similar variant was detected in another patient with restrictive cardiomyopathy at the age of 1.5 yr. From the age of a year patient's mother was worried about hyperhidrosis, tiredness and heavy breathing. There were noted atrium dilation and open foramen ovale. Besides, myocardial contractility is without changes with an additional systolic impulse. He presented with more prominent clinical signs of myopathy and involvement of central nervous system. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 01, 2019 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 08, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 12, 2020 | Not observed in large population cohorts (Lek et al., 2016); 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: 29858533, 32112656, 33060286, 21520333, 32154132, 26436962) - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 18, 2019 | - - |
Myofibrillar myopathy 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Abnormality of the musculature Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2022 | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 427928). This missense change has been observed in individual(s) with congenital myopathy and/or myofibrillar myopathy (PMID: 21520333, 26436962; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1186 of the FLNC protein (p.Ala1186Val). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at