Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_001267550.2(TTN):c.94507G>A(p.Ala31503Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000528 in 1,608,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A31503A) has been classified as Likely benign.
TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]
Uncertain significance, criteria provided, single submitter
clinical testing
New York Genome Center
Jan 25, 2022
The c.94507G>A (p.Ala31503Thr) missense variant in the TTN gene has not been reported in affected individuals in the literature. The variant has 0.00005042 allele frequency in the gnomAD (v2.1.1 and v3.1.2) database (14 out of 277666 heterozygous alleles, no homozygotes)suggesting it is not a common benign variant in the populations represented in that database. This variant is reported as a variant of uncertain significance and likely benign in the ClinVar database (Variation ID: 467664). The variant affects a highly conserved residue (Ala31503) located in the A-band domain of TTN protein (PMID:25589632) and multiple in silico tools provide conflicting predictions about the potential pathogenicity of this variant (CADD score = 35, REVEL score = 0.336). Based on the available evidence, the heterozygous c.94507G>A (p.Ala31503Thr) missense variant identified in the TTN gene is reported as a Variant of Uncertain Significance. -
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Oct 06, 2021
ACMG classification criteria: BP4 -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jun 10, 2016
The p.A22438T variant (also known as c.67312G>A), located in coding exon 167 of the TTN gene, results from a G to A substitution at nucleotide position 67312. The alanine at codon 22438 is replaced by threonine, an amino acid with similar properties, and is located in the A-band region of the N2-B isoform of the titin protein. This variant was previously reported in the SNPDatabase as rs375657115. Based on data from ExAC, the A allele has an overall frequency of < 0.01% (9/103545). The highest observed frequency was 0.02%% (3/11198) of Latino alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12030) total alleles studied and 0.01% (1/8236) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -