Submissions for variant NM_001267550.2(TTN):c.7061G>A (p.Arg2354His)

gnomAD frequency: 0.00287  dbSNP: rs75031300

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040635	SCV000064326	benign	not specified	2012-02-09	criteria provided, single submitter	clinical testing	T=38/C=3700 of AA chromosomes (NHLBI/ESP)
GeneDx	RCV000040635	SCV000236706	benign	not specified	2014-11-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000252219	SCV000318802	likely benign	Cardiovascular phenotype	2013-06-11	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.
Eurofins Ntd Llc (ga)	RCV000040635	SCV000333008	benign	not specified	2015-07-14	criteria provided, single submitter	clinical testing
Invitae	RCV000472312	SCV000555551	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770124	SCV000901550	likely benign	Cardiomyopathy	2017-09-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092342	SCV001248792	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	TTN: BS2
Illumina Laboratory Services, Illumina	RCV001131190	SCV001290800	benign	Dilated cardiomyopathy 1G	2017-10-11	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	RCV001131191	SCV001290801	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-10-11	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	RCV001131192	SCV001290802	benign	Tibial muscular dystrophy	2017-10-11	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	RCV001131193	SCV001290803	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-28	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	RCV001131194	SCV001290804	likely benign	Early-onset myopathy with fatal cardiomyopathy	2017-10-11	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040635	SCV001519586	benign	not specified	2021-03-01	criteria provided, single submitter	clinical testing	Variant summary: TTN c.7061G>A (p.Arg2354His) results in a non-conservative amino acid change located in the I-band domain 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 0.00091 in 281568 control chromosomes, predominantly at a frequency of 0.0092 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 24 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 a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely benign (n=3) and benign (n=3). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001092342	SCV004562054	benign	not provided	2023-09-06	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000040635	SCV001923447	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000040635	SCV001930062	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001092342	SCV001954201	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000040635	SCV001976119	benign	not specified		no assertion criteria provided	clinical testing