ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.21668G>A (p.Arg7223His)

gnomAD frequency: 0.00102  dbSNP: rs138853909
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039958 SCV000063649 likely benign not specified 2015-04-18 criteria provided, single submitter clinical testing p.Arg5979His in exon 71 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, 9 mammals and multiple birds and reptiles have a histidine (His) at this po sition despite high nearby amino acid conservation. It has been identified in 0. 16% (16/9726) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs138853909).
GeneDx RCV000039958 SCV000238301 likely benign not specified 2018-02-01 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.
Eurofins Ntd Llc (ga) RCV000713986 SCV000333386 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000269064 SCV000424334 benign Tibial muscular dystrophy 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina RCV000326449 SCV000424335 uncertain significance Early-onset myopathy with fatal cardiomyopathy 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000384905 SCV000424336 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000350254 SCV000424338 uncertain significance Dilated cardiomyopathy 1G 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000388473 SCV000424339 benign Myopathy, myofibrillar, 9, with early respiratory failure 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV001086766 SCV000555629 likely benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000713986 SCV000844642 likely benign not provided 2017-09-25 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000713986 SCV001153046 likely benign not provided 2023-07-01 criteria provided, single submitter clinical testing TTN: BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170080 SCV001332619 benign Cardiomyopathy 2018-01-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000039958 SCV001437214 benign not specified 2020-09-25 criteria provided, single submitter clinical testing Variant summary: TTN c.17936G>A (p.Arg5979His) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 143210 control chromosomes, predominantly at a frequency of 0.0023 within the African or African-American subpopulation in the gnomAD database (v3 genomes dataset). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6-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. c.17936G>A has been reported in the literature in an individual affected with Dilated Cardiomyopathy (Pugh_2014). This report however 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (2x), likely benign (4x), or VUS (2x). Based on the evidence outlined above, the variant was classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000713986 SCV004225905 uncertain significance not provided 2023-03-17 criteria provided, single submitter clinical testing BP4
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000713986 SCV001741209 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000039958 SCV001918507 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000713986 SCV001956116 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000713986 SCV001964052 likely benign not provided no assertion criteria provided clinical testing

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