7-128844769-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PP2PP3_StrongBP6BS2
The ENST00000325888.13(FLNC):c.3304C>T(p.Pro1102Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000325888.13 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.3304C>T | p.Pro1102Ser | missense_variant | 21/48 | ENST00000325888.13 | NP_001449.3 | |
FLNC | NM_001127487.2 | c.3304C>T | p.Pro1102Ser | missense_variant | 21/47 | NP_001120959.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.3304C>T | p.Pro1102Ser | missense_variant | 21/48 | 1 | NM_001458.5 | ENSP00000327145 | P3 | |
FLNC | ENST00000346177.6 | c.3304C>T | p.Pro1102Ser | missense_variant | 21/47 | 1 | ENSP00000344002 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000104 AC: 26AN: 249384Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 135346
GnomAD4 exome AF: 0.000247 AC: 361AN: 1461712Hom.: 0 Cov.: 34 AF XY: 0.000232 AC XY: 169AN XY: 727170
GnomAD4 genome AF: 0.000158 AC: 24AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2024 | Reported in at least one individual with HCM; however, p.(P1102S) was also identified in two control alleles (PMID: 28356264); 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 16, 2020 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 12, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2024 | The p.P1102S variant (also known as c.3304C>T), located in coding exon 21 of the FLNC gene, results from a C to T substitution at nucleotide position 3304. The proline at codon 1102 is replaced by serine, an amino acid with similar properties. This variant has been detected in a hypertrophic cardiomyopathy cohort, but was also detected in controls (Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10:). 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 04, 2024 | Variant summary: FLNC c.3304C>T (p.Pro1102Ser) results in a non-conservative amino acid change located in the Filamin/ABP280 repeat (IPR001298) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 249384 control chromosomes. The observed variant frequency is approximately 13.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Dilated Cardiomyopathy phenotype (7.8e-06). c.3304C>T has been reported in the literature a cohort of individuals with hypertrophic cardiomyopathy, but was also identified in healthy controls and classified as a polymorphism by the authors (Gomez_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28356264). ClinVar contains an entry for this variant (Variation ID: 539421). 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 | Labcorp Genetics (formerly Invitae), Labcorp | Dec 23, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at