Submissions for variant NM_001267550.2(TTN):c.14698G>A (p.Ala4900Thr)

gnomAD frequency: 0.00332  dbSNP: rs72648923

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172701	SCV000051451	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039861	SCV000063552	benign	not specified	2013-01-30	criteria provided, single submitter	clinical testing	Ala3656Thr in exon 47 of TTN: This variant is not expected to have clinical sign ificance because it has been identified in 0.3% (27/8226) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS), as well as in 3.2% (6/186) of Finnish chromosomes f rom a broad population by the 1000 Genomes Project (dbSNP rs72648923).
PreventionGenetics, part of Exact Sciences	RCV004528200	SCV000315400	benign	TTN-related disorder	2019-05-10	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ambry Genetics	RCV000247436	SCV000318618	benign	Cardiovascular phenotype	2013-05-02	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Eurofins Ntd Llc (ga)	RCV000039861	SCV000336584	benign	not specified	2015-10-15	criteria provided, single submitter	clinical testing
Invitae	RCV001084081	SCV000555382	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-02-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769086	SCV000900459	benign	Cardiomyopathy	2017-08-11	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852917	SCV000995659	benign	Long QT syndrome	2017-10-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172701	SCV001153090	benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	TTN: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172701	SCV001159140	benign	not provided	2020-02-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001129220	SCV001288728	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-08-16	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	RCV001129221	SCV001288729	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-08-16	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	RCV001129222	SCV001288730	benign	Early-onset myopathy with fatal cardiomyopathy	2017-08-16	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	RCV001129223	SCV001288731	benign	Tibial muscular dystrophy	2017-08-16	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	RCV001129224	SCV001288732	benign	Dilated cardiomyopathy 1G	2017-08-16	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039861	SCV001432112	benign	not specified	2020-08-17	criteria provided, single submitter	clinical testing	Variant summary: TTN c.10966G>A (p.Ala3656Thr) results in a non-conservative amino acid change located in the I-band of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 248448 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 9 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. To our knowledge, no occurrence of c.10966G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000172701	SCV000238204	not provided	not provided	2014-08-27	no assertion provided	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM,DCM-CRDM,CARDIOMYOPATHY panel(s).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172701	SCV001743909	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000039861	SCV001922221	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172701	SCV001929762	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000039861	SCV001958146	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172701	SCV001967051	likely benign	not provided		no assertion criteria provided	clinical testing