Submissions for variant NM_001267550.2(TTN):c.10088G>A (p.Arg3363His)

gnomAD frequency: 0.00077  dbSNP: rs148169214

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172723	SCV000055095	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039847	SCV000063538	likely benign	not specified	2012-12-18	criteria provided, single submitter	clinical testing	Arg3363His in exon 43 of TTN: This variant is not expected to have it clinical s ignificance because it has been identified in 0.2% (9/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/; dbSNP rs148169214) and due to a lack of conservati on across species, including mammals. Several other mammals (alpaca, dolphin, an d cow) carry a histidine (His; this variant) at this position supporting that th is change may be tolerated. Arg3363His in exon 43 of TTN (rs148169214; allele f requency = 0.2%, 9/4406)
GeneDx	RCV000172723	SCV000238075	likely benign	not provided	2020-10-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000172723	SCV000281091	uncertain significance	not provided	2016-04-08	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Invitae	RCV001081037	SCV000555124	likely 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)	RCV000039847	SCV000706708	likely benign	not specified	2017-03-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001129648	SCV001289188	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-06-15	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	RCV001129649	SCV001289189	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	RCV001129650	SCV001289190	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.
Illumina Laboratory Services, Illumina	RCV001129651	SCV001289191	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	RCV001134674	SCV001294425	benign	Tibial muscular dystrophy	2017-06-15	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	RCV000039847	SCV002014879	likely benign	not specified	2021-10-11	criteria provided, single submitter	clinical testing	Variant summary: TTN c.10088G>A (p.Arg3363His) results in a non-conservative amino acid change located in the I-band domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 282688 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5 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 occurrence of c.10088G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely benign (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002381318	SCV002694390	likely benign	Cardiovascular phenotype	2018-10-31	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.
Clinical Genetics, Academic Medical Center	RCV000039847	SCV001978812	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172723	SCV001980639	likely benign	not provided		no assertion criteria provided	clinical testing