rs145581345

Positions:

• chr2-178747588-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_133379.5(TTN):​c.14812A>G​(p.Met4938Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,268 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4 O:1
• Conservation: PhyloP100: 0.773

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015268564).
• BP6: Variant 2-178747588-T-C is Benign according to our data. Variant chr2-178747588-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47778.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, not_provided=1}. Variant chr2-178747588-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5	c.14812A>G	p.Met4938Val	missense_variant	46/46	ENST00000360870.10	NP_596870.2
TTN	NM_001267550.2	c.11311+5536A>G		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.14812A>G	p.Met4938Val	missense_variant	46/46	5	NM_133379.5	ENSP00000354117.4
TTN	ENST00000589042.5	c.11311+5536A>G		intron_variant		5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 151918 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000928

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000687 AC: 172 AN: 250446 Hom.: 1 AF XY: 0.000798 AC XY: 108 AN XY: 135320

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.00112 AC: 1643 AN: 1461232 Hom.: 1 Cov.: 34 AF XY: 0.00111 AC XY: 809 AN XY: 726926

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000546 AC: 83 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74330

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000928

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000684

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000610 AC: 74

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:4 Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TTN: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	clinical testing	GeneDx	Aug 29, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 07, 2022	The TTN c.14812A>G; p.Met4938Val variant (rs145581345; ClinVar Variation ID: 47778) is rare in the general population (<1% 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.Met4938Val 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). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke and Hamdani. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TTN p.Met4938Val variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs145581345) as “With Uncertain significance allele”. In ClinVar, there are conflicting interpretations of pathogenicity from four submitters: 2x uncertain significance (Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics), 1x likely benign (Biesecker Lab/Human Development Section, National Institutes of Health), and not provided (GeneDx). The variant was identified in control databases in 192 of 281816 chromosomes (1 homozygous) at a frequency of 0.000681 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 19 of 10342 chromosomes (freq: 0.001837), European (non-Finnish) in 145 of 128398 chromosomes (freq: 0.001129), Other in 7 of 7192 chromosomes (freq: 0.000973), African in 6 of 24944 chromosomes (freq: 0.000241), European (Finnish) in 5 of 25104 chromosomes (freq: 0.000199), South Asian in 5 of 30606 chromosomes (freq: 0.000163) and Latino in 5 of 35322 chromosomes (freq: 0.000142); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence however 2 of 4 in silico prediction software programs (SpliceSiteFinder and MaxEntScan) predict the creation of a new 3' splice site. The p.Met4938 residue is not conserved across mammals and other organisms and 3 of 3 computational analyses (PolyPhen-2, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 09, 2014

The Met4938Val variant in TTN has been identified by our laboratory in 1 Caucasi an adult with unspecified cardiomyopathy. This variant has also been identified in 0.13% (11/8600) of European American chromosomes by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; dbSNP rs145581345). Computational prediction tools and conservation analysis are limited or unavailable for this v ariant. In summary, additional studies are needed to fully assess the clinical s ignificance of the Met4938Val variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.92
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.044
Sift	Uncertain	0.015	D
Sift4G	Benign	0.39	T
Polyphen		0.0040	B
Vest4		0.45
MVP		0.58
ClinPred		0.0076	T
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs145581345; hg19: chr2-179612315;