Submissions for variant NM_001267550.2(TTN):c.39466C>A (p.Pro13156Thr)

gnomAD frequency: 0.00049  dbSNP: rs72650064

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154956	SCV000204638	uncertain significance	not specified	2014-06-30	criteria provided, single submitter	clinical testing	The Pro10722Thr variant in TTN has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 5/8168 of European American chrom osomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72650064). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Pro10722Thr variant is uncertain.
Eurofins Ntd Llc (ga)	RCV000724471	SCV000226545	uncertain significance	not provided	2015-02-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000724471	SCV000237131	likely benign	not provided	2021-04-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27662471)
Ambry Genetics	RCV000243216	SCV000318686	uncertain significance	Cardiovascular phenotype	2013-05-08	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Invitae	RCV001080889	SCV000555534	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-30	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852863	SCV000995597	likely benign	Cardiomyopathy; Supraventricular tachycardia	2017-10-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724471	SCV001152932	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	TTN: BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000154956	SCV001159752	uncertain significance	not specified	2019-04-07	criteria provided, single submitter	clinical testing	The TTN c.32164C>A; p.Pro10722Thr variant (rs72650064; ClinVar Variation ID: 178221) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Pro10722Thr variant cannot be determined with certainty.
Illumina Laboratory Services, Illumina	RCV001131898	SCV001291542	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.
Illumina Laboratory Services, Illumina	RCV001131899	SCV001291543	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	RCV001132870	SCV001292549	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	RCV001132871	SCV001292550	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	RCV001132872	SCV001292551	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798509	SCV002042463	benign	Cardiomyopathy	2019-10-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154956	SCV002074378	benign	not specified	2022-01-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.32164C>A (p.Pro10722Thr) results in a non-conservative amino acid change located in the I-band region, PEVK 22 domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00063 in 247548 control chromosomes, predominantly at a frequency of 0.0019 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.32164C>A has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence for causality (Kostareva_2016, Nunn_2016) and in an individual affected with distal myopathy in which the variant did not segregate with disease in the family (Liewluck_2017), evidence suggestive that the variant is benign. The variant of interest was found co-occurring with other one other known pathogenic variant (TNNI3 c.508C>T, p.Arg170Trp)(Kostareva_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: 4 classified the variant as of uncertain significance, 3 as likely benign, and 2 as benign. One submitter submitted both benign and VUS for different phenotypes. Based on the evidence outlined above, the variant was classified as benign.
Revvity Omics, Revvity	RCV000724471	SCV003819814	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544426	SCV004768462	likely benign	TTN-related disorder	2022-09-26	criteria provided, single submitter	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).
Blueprint Genetics	RCV000157561	SCV000207307	uncertain significance	Primary familial hypertrophic cardiomyopathy	2013-11-08	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000724471	SCV001741374	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000724471	SCV001918895	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000724471	SCV001926830	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000154956	SCV001954578	benign	not specified		no assertion criteria provided	clinical testing