Submissions for variant NM_001267550.2(TTN):c.3241G>A (p.Ala1081Thr)

dbSNP: rs55914517

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172732	SCV000051346	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040201	SCV000063892	uncertain significance	not specified	2014-07-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ala1081Thr vari ant in TTN has been identified by our laboratory in 2 adults with HCM, including one who carries a pathogenic variant in another gene. This variant has been ide ntified in 0.1% (9/8600) of European American chromosomes by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs59914517). Computati onal prediction tools and conservation analysis do not provide strong support fo r or against an impact to the protein. In summary, while the clinical significan ce of the Ala1081Thr variant is uncertain, its frequency suggests that it is mor e likely to be benign.
GeneDx	RCV000172732	SCV000237732	likely benign	not provided	2020-07-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17344846, 23861362)
Genetic Services Laboratory, University of Chicago	RCV000040201	SCV000249254	uncertain significance	not specified	2015-04-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085560	SCV000286578	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000253970	SCV000318004	uncertain significance	Cardiovascular phenotype	2012-11-19	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Eurofins Ntd Llc (ga)	RCV000040201	SCV000333906	likely benign	not specified	2016-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001129772	SCV001289315	benign	Tibial muscular dystrophy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001132481	SCV001292141	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001132482	SCV001292142	uncertain significance	Dilated cardiomyopathy 1G	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001132483	SCV001292143	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001132484	SCV001292144	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170662	SCV001333256	likely benign	Cardiomyopathy	2020-09-04	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001129772	SCV001369633	uncertain significance	Tibial muscular dystrophy	2019-09-13	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040201	SCV001426870	likely benign	not specified	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.3241G>A (p.Ala1081Thr) results in a non-conservative amino acid change located in the near Z-disk region (cardiodb.org) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 251122 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 1.7- fold the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is benign. c.3241G>A has been reported in the literature in at least one individual affected with Hypertrophic Cardiomyopathy (e.g. Campuzano_2015, Mademont-Soler_2017). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Co-occurrence with another pathogenic variant has been reported in the literature (MYBPC3 c.2512G>T, p.E838X; Mademont-Soler_2017), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other 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, including uncertain significance (n=3), likely benign (n=4), and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000172732	SCV001500699	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TTN: BP4
Athena Diagnostics	RCV000040201	SCV001880241	benign	not specified	2020-10-15	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172732	SCV001743765	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172732	SCV001918801	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172732	SCV001953543	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172732	SCV001972008	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534896	SCV004719050	likely benign	TTN-related disorder	2019-08-03	no assertion criteria provided	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).