Submissions for variant NM_001267550.2(TTN):c.97760G>A (p.Arg32587His)

dbSNP: rs55704830

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000154034	SCV000051469	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040857	SCV000064548	likely benign	not specified	2015-09-14	criteria provided, single submitter	clinical testing	p.Arg30019His in exon 299 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.5% (61/10980) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs55704830).
GeneDx	RCV000154034	SCV000237840	benign	not provided	2020-06-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18948003, 1745277, 12669942, 23861362, 24105469, 24395473, 21810661, 22335739, 23418287, 23518707, 21617319, 10462489, 11717165, 12145747, 17444505)
Invitae	RCV001080383	SCV000286947	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000040857	SCV000333098	likely benign	not specified	2015-07-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000295583	SCV000420513	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-07-25	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	RCV000313220	SCV000420516	benign	Tibial muscular dystrophy	2017-07-25	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000154034	SCV000610530	likely benign	not provided	2017-06-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000154034	SCV000892595	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TTN: BP4, BP5, BS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769864	SCV000901290	benign	Cardiomyopathy	2020-01-27	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000769864	SCV000995508	likely benign	Cardiomyopathy	2017-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040857	SCV001442619	likely benign	not specified	2020-10-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.90056G>A (p.Arg30019His) results in a non-conservative amino acid change located in the A- band region (cardiodb.org) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 167792 control chromosomes. The observed variant frequency is approximately 4.4- fold 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.90056G>A has been reported in the literature in at least one individual affected with Dilated Cardiomyopathy without strong evidence for causality (e.g. Headrick_2018). This report does 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. 11 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 (uncetain significance, n=3; benign/likely benign, n=8). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000154034	SCV001474151	likely benign	not provided	2023-12-19	criteria provided, single submitter	curation
Athena Diagnostics	RCV000040857	SCV001879727	benign	not specified	2021-03-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362659	SCV002662114	likely benign	Cardiovascular phenotype	2018-06-01	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.