rs780829334
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2
The NM_001458.5(FLNC):c.4991C>T(p.Thr1664Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,970 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1664T) has been classified as Likely benign.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.4991C>T | p.Thr1664Met | missense_variant | 30/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.4991C>T | p.Thr1664Met | missense_variant | 30/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.4991C>T | p.Thr1664Met | missense_variant | 30/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.4991C>T | p.Thr1664Met | missense_variant | 30/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000722 AC: 18AN: 249232Hom.: 0 AF XY: 0.0000887 AC XY: 12AN XY: 135268
GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461758Hom.: 1 Cov.: 36 AF XY: 0.0000688 AC XY: 50AN XY: 727178
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74348
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 09, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2019 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31918855) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 14, 2020 | - - |
Hypertrophic cardiomyopathy 26 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 09, 2022 | The p.T1664M variant (also known as c.4991C>T), located in coding exon 30 of the FLNC gene, results from a C to T substitution at nucleotide position 4991. The threonine at codon 1664 is replaced by methionine, an amino acid with similar properties. This variant has been detected in individuals from dilated cardiomyopathy and left ventricular noncompaction cohorts; however, clinical details were limited, and other genetic variants were detected in the latter case (Liu S et al. Int J Cardiol. 2020 03;302:117-123; Mori V et al. Int J Cardiol Heart Vasc. 2022 Jun;40:101023). This variant was also detected in an individual from a suspected drug-induced arrhythmia and sudden death cohort, and in an individual with short stature, brachydactyly, intellectual and developmental disability and seizures syndrome who also had a mutation in the PRMT7 gene and reportedly normal echocardiogram (Martinez-Matilla M et al. Forensic Sci Int Genet, 2019 09;42:203-212; Agolini E et al. Clin. Genet., 2018 03;93:675-681). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 29, 2024 | Variant summary: FLNC c.4991C>T (p.Thr1664Met) results in a non-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 7.2e-05 in 249232 control chromosomes. The observed variant frequency is approximately 6.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Cardiomyopathy phenotype (1.1e-05), strongly suggesting that the variant is benign. c.4991C>T has been reported in the literature in individuals affected with Cardiomyopathy (Liu_2020, Modena_2020, Mori_2022). However, in most cases, variants in other genes associated with Cardiomyopathy were also identified. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31918855, 32101375, 35463915). ClinVar contains an entry for this variant (Variation ID: 432545). Based on the evidence outlined above, the variant was classified as likely benign. - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at