Submissions for variant NM_001267550.2(TTN):c.95270T>C (p.Ile31757Thr)

gnomAD frequency: 0.00048  dbSNP: rs72648259

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000082452	SCV000054882	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000082452	SCV000114481	uncertain significance	not provided	2018-05-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154888	SCV000204570	uncertain significance	not specified	2013-09-20	criteria provided, single submitter	clinical testing	The Ile29189Thr variant in TTN has now been identified by our laboratory in 2 in dividuals with cardiomyopathy (1 child with WPW and clinical features of Danon d isease and 1 infant with cardiomyopathy). It has also been identified in 2/8370 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS/; dbSNP rs72648259). Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provi de strong support for or against an impact to the protein. At this time, additio nal information is needed to fully assess the clinical significance of this vari ant.
GeneDx	RCV000082452	SCV000237803	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	Reported in individuals with DCM or HCM, although most probands harbored additional cardiogenetic variants; of note, this variant is also described as I22692T and I30116T due to the use of alternate transcripts (Lopes et al., 2013; Begay et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24636144, 26567375, 23861362, 23396983)
Illumina Laboratory Services, Illumina	RCV000312560	SCV000420685	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-13	criteria provided, single submitter	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.
Illumina Laboratory Services, Illumina	RCV000369634	SCV000420686	benign	Tibial muscular dystrophy	2018-01-13	criteria provided, single submitter	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.
Illumina Laboratory Services, Illumina	RCV000317322	SCV000420688	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-13	criteria provided, single submitter	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.
Illumina Laboratory Services, Illumina	RCV000355719	SCV000420689	uncertain significance	Dilated cardiomyopathy 1G	2018-01-13	criteria provided, single submitter	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.
Illumina Laboratory Services, Illumina	RCV000263196	SCV000420690	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-13	criteria provided, single submitter	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.
Invitae	RCV000465970	SCV000542824	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000082452	SCV001152641	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	TTN: BP1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170760	SCV001333366	likely benign	Cardiomyopathy	2018-03-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000082452	SCV001713207	uncertain significance	not provided	2020-08-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362734	SCV002666318	likely benign	Cardiovascular phenotype	2020-04-01	criteria provided, single submitter	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.
Revvity Omics, Revvity	RCV000082452	SCV003825608	uncertain significance	not provided	2022-06-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154888	SCV004099965	likely benign	not specified	2023-09-18	criteria provided, single submitter	clinical testing	Variant summary: TTN c.87566T>C (p.Ile29189Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 248652 control chromosomes, predominantly at a frequency of 0.00057 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 1.46 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.87566T>C has been reported in the literature in individuals affected with dilated cardiomyopathy, hypertrophic cardiomyopathy, and a stillbirth case without strong evidence of causality (Lopes_2013, Begay_2015, Campuzano_2015, Sahlin_2018). These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 23396983, 26567375, 26516846, 30615648). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign/likely benign (n=4) or uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004529869	SCV004739239	uncertain significance	TTN-related disorder	2024-02-14	criteria provided, single submitter	clinical testing	The TTN c.95270T>C variant is predicted to result in the amino acid substitution p.Ile31757Thr. This variant was reported in individuals with hypertrophic or dilated cardiomyopathy and also in a stillbirth cohort (described as p.Ile22692Thr in transcript NM_003319 in Table S1, Lopes et al. 2013. PubMed ID: 23396983; described as p.Ile29189Thr in transcript NM_133378 in Table S1, Campuzano et al. 2015. PubMed ID: 26516846; Begay et al. 2015. PubMed ID: 26567375; Table S2, Sahlin et al. 2019. PubMed ID: 30615648). This variant is reported in 0.056% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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.