chr7-128846396-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001458.5(FLNC):c.4060C>T(p.Arg1354Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,232 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001458.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.4060C>T | p.Arg1354Ter | stop_gained | 23/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.4060C>T | p.Arg1354Ter | stop_gained | 23/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.4060C>T | p.Arg1354Ter | stop_gained | 23/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.4060C>T | p.Arg1354Ter | stop_gained | 23/47 | 1 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458232Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 725610
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32112656, 28436997) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2021 | The p.R1354* pathogenic mutation (also known as c.4060C>T), located in coding exon 23 of the FLNC gene, results from a C to T substitution at nucleotide position 4060. This changes the amino acid from an arginine to a stop codon within coding exon 23. This mutation was reported in an individual with familial dilated cardiomyopathy (Janin A et al. Clin Genet, 2017 Dec;92:616-623). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
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 | Aug 07, 2021 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 28436997). ClinVar contains an entry for this variant (Variation ID: 70588). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg1354*) in the FLNC gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at