chr2-178766597-G-A

Position:

• chr2-178766597-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_001267550.2(TTN):​c.9487C>T​(p.Arg3163Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,562 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).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 3.22

Genes affected

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08272371).
• BP6: Variant 2-178766597-G-A is Benign according to our data. Variant chr2-178766597-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47651.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.9487C>T	p.Arg3163Cys	missense_variant	41/363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.9487C>T	p.Arg3163Cys	missense_variant	41/46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.9487C>T	p.Arg3163Cys	missense_variant	41/363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.9487C>T	p.Arg3163Cys	missense_variant	41/46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 250432 Hom.: 0 AF XY: 0.0000739 AC XY: 10 AN XY: 135336

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000382

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461322 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727006

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74438

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000361 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2020	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 05, 2017	p.Arg3163Cys (c.9487C>T) in exon 41 of the TTN gene (NM_133378.4; 2:179631324) Given that the uncertain clinical significance of missense variants in TTN and this variant’s high frequency in the general population, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). It is unclear at this time what role, if any, TTN missense variants play in causing inherited cardiovascular disese. While truncating (nonsense, frameshift, etc.) variants in TTN have been implicated in dilated cardiomyopathy, the impact of missense variants in this gene remains unclear. In general population samples there is a high prevalence of rare or novel TTN missense variants, making it likely that testing anyone with this panel would uncover such a variant. As such we would generally consider all TTN missense variants to be variants of uncertain significance. The variant has been seen in at least 3 unrelated cases of heart disease (not including this patient's family). These are all cases from labs: -LMM has seen this variant in 2 adults, one with concentric LVH and another with atrial fibrillation. -This variant is reported in ClilnVar. GeneDx also classifies this variant as a variant of uncertain significance. -Per Cardiodb, this variant is "unlikely to be pathogenic" based on population frequency in large population databases. This variant has not been published in the literature. Per the test report, "computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity." The arginine at codon 3163 is completely conserved across species, and neighboring amino acids are well-conserved. Other nearby variants are classified as either (likely) benign or as variants of uncertain significance (Arg3163His, Gln3162Arg). The variant was reported online in 31 of 138,071 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 23 of 12,014 individuals of African descent (MAF=0.09%), 6 of 9,400 individuals of East Asian descent, 1 of 17,186 individuals of Latino descent and 1 of 62,943 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	The TTN c.9487C>T; p.Arg3163Cys variant (rs140664731; ClinVar Variation ID: 47651) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Arg3163Cys variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 15, 2022	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Arg3163Cys va riant in TTN has been identified by our laboratory in 2 adults with concentric L VH and atrial fibrillation. This variant has also been identified in 0.1% (23/24 028) of African chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs140664731). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary , while the clinical significance of the p.Arg3163Cys variant is uncertain, its frequency suggests that it is more likely to be benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2023	- -

TTN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2023

The TTN c.9487C>T variant is predicted to result in the amino acid substitution p.Arg3163Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179631324-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Benign	0.97
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.083	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.041	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.3	D;D;.;.;D;D;.;D
REVEL	Uncertain	0.56
Sift	Benign	0.035	D;D;.;.;D;D;.;D
Sift4G	Pathogenic	0.0010	.;.;.;.;.;.;.;D
Polyphen		1.0	.;.;.;D;.;.;D;D
Vest4		0.35
MVP		0.71
MPC		0.54
ClinPred		0.20	T
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140664731; hg19: chr2-179631324;