Submissions for variant NM_001267550.2(TTN):c.87412C>A (p.Pro29138Thr)

gnomAD frequency: 0.00073  dbSNP: rs72648227

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172625	SCV000051285	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040733	SCV000064424	uncertain significance	not specified	2014-08-21	criteria provided, single submitter	clinical testing	The Pro26570Thr variant in TTN has been identified by our laboratory in 1 indivi dual with HCM and 2 individuals with DCM. This variant has also been identified in 0.2% (4/2178) of chromosomes of various ethnicities by the 1000 Genomes Proje ct (dbSNP rs72648227). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summar y, the clinical significance of the Pro26570Thr variant is uncertain.
GeneDx	RCV000172625	SCV000237679	benign	not provided	2020-04-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23396983, 27930701, 23861362, 29886034)
Invitae	RCV001086492	SCV000286886	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-30	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000040733	SCV000297083	uncertain significance	not specified	2015-09-18	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000040733	SCV000334280	likely benign	not specified	2015-08-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618830	SCV000735529	likely benign	Cardiovascular phenotype	2018-05-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CeGaT Center for Human Genetics Tuebingen	RCV000172625	SCV001152692	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TTN: BS2
Illumina Laboratory Services, Illumina	RCV001129291	SCV001288807	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-12	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	RCV001129292	SCV001288808	uncertain significance	Dilated cardiomyopathy 1G	2018-01-12	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	RCV001131993	SCV001291644	benign	Tibial muscular dystrophy	2018-01-12	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	RCV001131994	SCV001291645	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-12	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	RCV001131995	SCV001291646	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-12	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.
Genetics and Genomics Program, Sidra Medicine	RCV001293177	SCV001434175	likely benign	Primary dilated cardiomyopathy		criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040733	SCV001623107	likely benign	not specified	2021-04-26	criteria provided, single submitter	clinical testing	Variant summary: TTN c.79708C>A (p.Pro26570Thr) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 248134 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 3 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 benign. c.79708C>A has been reported in the literature in individuals affected with HCM, LQT or Sudden Unexplained Death (Lopes_2013, Campuzano_2015). 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=5, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798189	SCV002043031	benign	Cardiomyopathy	2020-05-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172625	SCV001932696	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000040733	SCV001978977	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172625	SCV001979604	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172625	SCV002038018	likely benign	not provided		no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002227443	SCV002507120	likely pathogenic	Tip-toe gait		no assertion criteria provided	clinical testing