rs33997263
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong
The NM_001267550.2(TTN):āc.9571C>Gā(p.Gln3191Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q3191K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.9571C>G | p.Gln3191Glu | missense_variant | 41/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.9571C>G | p.Gln3191Glu | missense_variant | 41/46 | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.9571C>G | p.Gln3191Glu | missense_variant | 41/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.9571C>G | p.Gln3191Glu | missense_variant | 41/46 | 5 | NM_133379.5 | ||
TTN-AS1 | ENST00000659121.1 | n.1592+2145G>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000757 AC: 19AN: 251074Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135690
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727210
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74430
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 17, 2012 | Variant classified as Uncertain Significance - Favor Benign. The Gln3191Glu vari ant in TTN has not been reported in the literature nor previously identified by our laboratory. It has been identified in 1/94 Han Chinese chromosomes from a b road population by the 1000 Genomes project (dbSNP rs33997263). Computational a nalyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Lys32641Gln variant may not impact the protein and se veral other species (including rat, birds, amphibians, and fish) carry a glutami c acid (Glu; this variant) despite high amino acid conservation nearby, suggesti ng that this variant may be tolerated, though this information is not predictive enough to rule out pathogenicity. This variant is more likely benign but at thi s time, additional information is needed to fully assess its clinical significan ce. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 2014 | Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s). - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2017 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 25, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 20, 2013 | The p.Q3191E variant (also known as c.9571C>G) is located in coding exon 40 of the TTN gene. This alteration results from a C to G substitution at nucleotide position 9571. The glutamine at codon 3191 is replaced by glutamic acid, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs33997263. Based on data from the 1000 Genomes Project, the G-allele has an overall frequency of approximately 0.05% (1/2184). The highest observed frequency was 0.52% (1/194) Han Chinese chromosomes studied. This amino acid position is poorly conserved on sequence alignment. This variant is predicted to be benign by PolyPhen in silico analyses. Since supporting evidence is limited at this time, the clinical significance of p.Q3191E remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at