rs199531140

Variant names:

• chr2-178528662-C-G
• rs199531140
• NM_001267550.2:c.107089G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.107089G>C​(p.Glu35697Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,613,154 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:9
• Conservation: PhyloP100: 2.67
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011174649).
• BP6: Variant 2-178528662-C-G is Benign according to our data. Variant chr2-178528662-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191806.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000162 (237/1460876) while in subpopulation SAS AF = 0.00189 (163/86104). AF 95% confidence interval is 0.00166. There are 3 homozygotes in GnomAdExome4. There are 165 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.107089G>C	p.Glu35697Gln	missense_variant	Exon 360 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.107089G>C	p.Glu35697Gln	missense_variant	Exon 360 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000336 AC: 83 AN: 247288 AF XY: 0.000477

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1460876 Hom.: 3 Cov.: 32 AF XY: 0.000227 AC XY: 165 AN XY: 726658

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000897 AC: 4 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111474

Other (OTH) AF: 0.000199 AC: 12 AN: 60344

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74472

African (AFR) AF: 0.0000241 AC: 1 AN: 41550

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000359 AC: 3

ExAC AF: 0.000471 AC: 57

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BP4 -

Jul 10, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:2

Apr 23, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.99385G>C (p.Glu33129Gln) results in a conservative amino acid change located in the M-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 247288 control chromosomes (gnomAD), predominantly at a frequency of 0.0021 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.99385G>C in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, four as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Jul 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu33129Gln in exon 309 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.3% (42/15700) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs199531140). -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dilated cardiomyopathy 1G Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

TTN-related disorder Benign:1

Jun 13, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tibial muscular dystrophy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 02, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.17
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.83
Eigen	Benign	0.049
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.2	.;.;.;M;.;.;M
PhyloP100		2.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;N;.;.;N;N;.
REVEL	Benign	0.070
Sift	Benign	0.19	.;T;.;.;T;T;.
Polyphen		0.22	.;.;.;B;.;.;B
Vest4		0.33
MVP		0.20
MPC		0.091
ClinPred		0.026	T
GERP RS		4.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs199531140; hg19: chr2-179393389;