rs530537991

chr2-178530896-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001267550.2(TTN):c.105719G>A(p.Arg35240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R35240W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.927

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 -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.02643004).
• BP6: Variant 2-178530896-C-T is Benign according to our data. Variant chr2-178530896-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178891.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}. Variant chr2-178530896-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.105719G>A	p.Arg35240Gln	missense_variant	358/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.220-4836C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.105719G>A	p.Arg35240Gln	missense_variant	358/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.416+7260C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151678 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

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: 0.0000683 AC: 17 AN: 248806 Hom.: 0 AF XY: 0.0000815 AC XY: 11 AN XY: 134948

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1461698 Hom.: 0 Cov.: 34 AF XY: 0.0000495 AC XY: 36 AN XY: 727126

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151796 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74190

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000745 AC: 9

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 01, 2019	The c.98015G>A; p.Arg32672Gln variant (rs530537991) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.006 percent (identified on 18 out of 280,138 chromosomes) and has been reported to the ClinVar database (Variation ID: 178891). This is a missense variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site/weakening the nearby canonical splice site. Altogether, there is not enough evidence to classify the p.Arg32672Gln variant with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2015	p.Arg32672Gln in exon 307 of TTN: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, 5 mammals (gibbon, bat, microbat, big brown bat, and platypus) have a glu tamine (Gln) at this position despite high nearby amino acid conservation. This variant has been identified in 4/8620 East Asian chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs530537991). -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2020	This variant is associated with the following publications: (PMID: 23396983) -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2016

This sequence change replaces arginine with glutamine at codon 35240 of the TTN protein (p.Arg35240Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs530537991, ExAC 0.05%) but has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 178891). Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with unknown impact on protein function. Missense variants in this region of the TTN gene are typically not causative for cardiac disease, but may be relevant for neuromuscular disorders. However, the available evidence is currently insufficient to determine this variant’s role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

TTN-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2022

The TTN c.105719G>A variant is predicted to result in the amino acid substitution p.Arg35240Gln. This variant was reported along with a second TTN variant in an individual with hypertrophic cardiomyopathy (described as p.R26175Q in NM_003319, Patient H109 in Table S4, Lopes et al. 2013. PubMed ID: 23396983). This variant was also reported in an individual with pediatric dilated cardiomyopathy; however, this individual also harbored additional variants in cardiomyopathy-related genes (Patient 477 in Table S2, Burstein et al. 2021. PubMed ID: 32746448). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179395623-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2020

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	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	15
Dann	Benign	0.85
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.86	D;D;D;.;T;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.026	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.2	N;N;.;.;N;N;.
REVEL	Benign	0.038
Sift	Benign	0.082	T;T;.;.;T;T;.
Polyphen		0.0070	.;.;.;B;.;.;B
Vest4		0.12
MutPred		0.35		.;.;.;Loss of MoRF binding (P = 0.0264);.;.;Loss of MoRF binding (P = 0.0264);
MVP		0.088
MPC		0.097
ClinPred		0.042	T
GERP RS		2.9

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: rs530537991; hg19: chr2-179395623; COSMIC: COSV60011515; COSMIC: COSV60011515;