rs199632397

Positions:

• chr2-178529076-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.106675G>C​(p.Glu35559Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,613,336 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 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 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:11
• Conservation: PhyloP100: 1.61

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.021069646).
• BP6: Variant 2-178529076-C-G is Benign according to our data. Variant chr2-178529076-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192135.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=8, Benign=3}. Variant chr2-178529076-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.106675G>C	p.Glu35559Gln	missense_variant	360/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.219+5440C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.106675G>C	p.Glu35559Gln	missense_variant	360/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.416+5440C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000426 AC: 106 AN: 248704 Hom.: 0 AF XY: 0.000504 AC XY: 68 AN XY: 134968

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000470

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.000379 AC: 554 AN: 1461086 Hom.: 3 Cov.: 32 AF XY: 0.000405 AC XY: 294 AN XY: 726800

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.000332

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74412

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000275 AC: 1

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.000414 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TTN: BP4 -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	This variant is associated with the following publications: (PMID: 27930701, 23861362, 28440294) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 04, 2023	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 10, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Glu32991Gln v ariant has been identified by our laboratory in 1 Caucasian individual with idio pathic cardiomyopathy and in 0.1% (34/30728) of South Asian chromosomes by the G enome Aggreagation Database (gnomAD, http://gnomad.broadinstitute.org/, dbSNP rs 199632397). This variant was also identified in a 23-year-old female who died su ddenly; however, the specific cause of her death was unexplained even after auto psy (Sanchez 2016). This variant has also been reported in ClinVar (Variation ID 192135). Computational prediction tools and conservation analysis suggest that the p.Glu32991Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Glu32991Gln variant is uncertain, its frequency suggests that it is more likely to be benign. -

Cardiovascular phenotype Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2013	There is insufficient or conflicting evidence for classification of this alteration. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 04, 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

TTN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2023

The TTN c.106675G>C variant is predicted to result in the amino acid substitution p.Glu35559Gln. This variant, along with two additional TTN variants, was reported in one case of sudden death, however no additional studies were performed to help assess the pathogenicity of this variant (described as c.98971G>C (p.Glu32991Gln) with an alternate transcript NM_133378, Sanchez et al. 2016. PubMed ID: 27930701). This variant is reported in 0.11% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179393803-C-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2017

- -

Dilated cardiomyopathy 1G Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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. -

TTN-related myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 22, 2021

The TTN c.106675G>C (p.Glu35559Gln) variant is a missense variant. The p.Glu35559Gln variant has been reported in one publication in which it is described as c.98971G>C (p.Glu32991Gln). The variant was identified in a heterozygous state in a 23 year-old female with sudden unexplained death. The p.Glu35559Gln variant has not been reported in association with autosomal dominant or recessive TTN-related myopathies. The p.Glu35559Gln variant is reported at a frequency of 0.001146 in the South Asian population of the Genome Aggregation Database. Although this frequency is too high to suggest an association with dominant TTN-related phenotypes, it is consistent with a potential association with autosomal recessive phenotypes. This variant is located within the M band of the protein. In silico prediction of pathogenicity for this variant are mixed, but lean towards benign. However, currently available in silico prediction tools may have limited utility in the assessment of missense variants in the TTN gene (Rees et al. 2021). Based on the limited evidence and application of the ACMG criteria, the p.Glu35559Gln variant is classified as a variant of uncertain significance for TTN-related myopathy. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 24, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.85
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T;T;.;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.021	T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.97	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N;N;.;.;N;N;.
REVEL	Benign	0.098
Polyphen		0.60	.;.;.;P;.;.;P
Vest4		0.26
MVP		0.35
MPC		0.12
ClinPred		0.026	T
GERP RS		5.5

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: rs199632397; hg19: chr2-179393803;