rs142304137

Positions:

• chr2-178749036-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.13364A>G​(p.Lys4455Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 1,611,782 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 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 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 0.379

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: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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026657552).
• BP6: Variant 2-178749036-T-C is Benign according to our data. Variant chr2-178749036-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47753.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr2-178749036-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.13364A>G	p.Lys4455Arg	missense_variant	46/46	ENST00000360870.10	NP_596870.2
TTN	NM_001267550.2	c.11311+4088A>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.13364A>G	p.Lys4455Arg	missense_variant	46/46	5	NM_133379.5	ENSP00000354117
TTN	ENST00000589042.5	c.11311+4088A>G		intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.1223+6066T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 151930 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000592

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000409 AC: 102 AN: 249134 Hom.: 0 AF XY: 0.000437 AC XY: 59 AN XY: 135098

Gnomad AFR exome AF: 0.0000641

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000505

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000556 AC: 811 AN: 1459734 Hom.: 1 Cov.: 35 AF XY: 0.000571 AC XY: 415 AN XY: 726228

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000755

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000626

Gnomad4 OTH exome AF: 0.000514

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74338

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000591

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000538 Hom.: 0

Bravo AF: 0.000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000437

EpiControl AF: 0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2019	This variant is associated with the following publications: (PMID: 23476865) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TTN p.Lys4455Arg variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs142304137), ClinVar (conflicting interpretations of pathogenicity, associated with syncope and hypertrophic cardiomyopathy; classified as Uncertain Significance by Laboratory for Molecular Medicine at Partners Healthcare, Centre for Mendelian Genomics at University Medical Centre Ljubljana, EGL Genetic Diagnostics and classified as Likely Benign by GeneDx), and LOVD 3.0. The variant was not identified in the Cosmic database. The variant was identified in control databases in 110 of 280462 chromosomes at a frequency of 0.000392 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: South Asian in 30 of 30546 chromosomes (freq: 0.000982), European (non-Finnish) in 62 of 128212 chromosomes (freq: 0.000484), Other in 3 of 7108 chromosomes (freq: 0.000422), Latino in 13 of 35210 chromosomes (freq: 0.000369), African in 2 of 24318 chromosomes (freq: 0.000082), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant was identified in a 5 year old asymptomatic female who presented with sinus bradycardia and was found to have exercise-induced bidirectional VT and a hypertrabeculated left ventricle (Egan_2013_PMID: 23476865). A pan cardiomyopathy microarray identified three missense variants in this individual: RYR2 p.Arg169Gln, CASQ2 p.Asp398del, and TTN p.Lys4455Arg (Egan_2013_PMID: 23476865). Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing, specificically a decrease in 5’ splicing activity at the variant location. However, this information is not predictive enough to assume 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. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TTN: BP4 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 27, 2013

The Lys4455Arg variant in TTN has been identified by our laboratory in 1 Caucasi an individual with LVNC and bidirectional VT and has been identified in 1/8588 E uropean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs142304137). Computational analyses are limited or unavailable for this variant. Additional information is needed to fully assess its clinical significance. -

Hypertrophic cardiomyopathy;C0039070:Syncope Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 29, 2015

- -

Tibial muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.8
DANN	Uncertain	0.99
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.00031
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.21	T
Polyphen		0.87	P
Vest4		0.13
MVP		0.60
ClinPred		0.075	T
GERP RS		6.0

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: rs142304137; hg19: chr2-179613763;