rs150667217

Positions:

• chr2-178780124-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.3605T>C​(p.Val1202Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000651 in 1,613,700 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:5 O:1
• Conservation: PhyloP100: 6.27

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15962744).
• BP6: Variant 2-178780124-A-G is Benign according to our data. Variant chr2-178780124-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166325.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=3, not_provided=1, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.3605T>C	p.Val1202Ala	missense_variant	22/363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.3605T>C	p.Val1202Ala	missense_variant	22/46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.3605T>C	p.Val1202Ala	missense_variant	22/363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.3605T>C	p.Val1202Ala	missense_variant	22/46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 250870 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135594

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000694 AC: 1015 AN: 1461596 Hom.: 1 Cov.: 30 AF XY: 0.000670 AC XY: 487 AN XY: 727118

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000875

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74294

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000398 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1 Other:1

not provided, no classification provided	clinical testing	GeneDx	Apr 02, 2014	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TTN: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 16, 2022	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2015	The p.Val1202Ala variant in TTN has been previously identified by our laboratory in 1 adult with ARVC. It has been identified in 22/66680 of European chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs150667217). Valine (Val) at position 1202 is not conserved in mammals or ev olutionarily distant species and 1 mammal (Tibetan antelope) carries an alanine (Ala) at this position, raising the possibility that this change may be tolerate d. Additional computational prediction tools do not provide strong evidence for or against an impact to the protein. In summary, the clinical significance of th e p.Val1202Ala variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 15, 2024	Variant summary: TTN c.3605T>C (p.Val1202Ala) results in a non-conservative amino acid change located in the Z-disk region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 282266 control chromosomes (gnomAD), predominantly at a frequency of 0.0004 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.0004 vs 0.00039), allowing no conclusion about variant significance. c.3605T>C has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy without strong evidence for causality (Lopes_2013). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23396983). ClinVar contains an entry for this variant (Variation ID: 166325). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 26, 2017

- -

Dilated cardiomyopathy 1G Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 23, 2019

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Tibial muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 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	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;D;T;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N;N;.;.;N;N;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.014	D;D;.;.;D;D;.;T
Sift4G	Uncertain	0.0020	.;.;.;.;.;.;.;D
Polyphen		1.0, 1.0	.;.;.;D;.;.;D;D
Vest4		0.18
MVP		0.48
MPC		0.50
ClinPred		0.067	T
GERP RS		5.8

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: rs150667217; hg19: chr2-179644851; COSMIC: COSV60207841; COSMIC: COSV60207841;