ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.102271C>T (p.Arg34091Trp)

gnomAD frequency: 0.00095  dbSNP: rs140319117
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Total submissions: 22
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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 RCV000154875 SCV000204557 likely benign not specified 2017-06-05 criteria provided, single submitter clinical testing p.Arg31523Trp in exon 307 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.3% (33/10126) of Ashkenazi Jewi sh chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org/; dbSNP rs140319117).
Eurofins NTD LLC (GA) RCV000713953 SCV000229375 uncertain significance not provided 2018-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000713953 SCV000236911 likely benign not provided 2020-08-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24055113, 24231549, 15802564, 24569025, 23514108, 23446887, 24625729, 26272908, 23486992, 24271327, 24578547, 28009443, 28256728, 27194543, 23861362, 33232181)
Invitae RCV001086721 SCV000555083 likely benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621822 SCV000735076 likely benign Cardiovascular phenotype 2019-11-21 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Athena Diagnostics Inc RCV000154875 SCV000844602 benign not specified 2020-06-29 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852776 SCV000995499 likely benign Primary dilated cardiomyopathy; Heart failure 2018-07-03 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001134221 SCV001293954 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services,Illumina RCV000119019 SCV001293955 benign Myopathy, myofibrillar, 9, with early respiratory failure 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services,Illumina RCV001134222 SCV001293956 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services,Illumina RCV000509179 SCV001293957 benign Tibial muscular dystrophy 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services,Illumina RCV001134223 SCV001293958 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154875 SCV001748673 likely benign not specified 2021-06-21 criteria provided, single submitter clinical testing Variant summary: TTN c.94567C>T (p.Arg31523Trp) results in a non-conservative amino acid change located in the M-band domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 247286 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.84 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 Non-Finnish European origin. c.94567C>T was initially reported to segregate with disease in two families with hereditary myopathy with early respiratory failure (HMERF; Lange_2005). However, subsequent reports have reported a missense mutation in the fibronectin-like FN3 119 domain of A-band titin in several Swedish families with HMERF (Ohlsson et al., 2012) including the patients reported in Lange_2005, which suggests the second mutation as the likely candidate for pathogenicity in the two initial families reported (Hedberg_2014). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Lange_2005). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six labs classified the variant as likely benign/benign while three classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen RCV000713953 SCV001962319 uncertain significance not provided 2021-12-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798505 SCV002043110 benign Cardiomyopathy 2020-06-08 criteria provided, single submitter clinical testing
GeneReviews RCV000119019 SCV000153721 uncertain significance Myopathy, myofibrillar, 9, with early respiratory failure 2014-02-27 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000509179 SCV000607067 not provided Tibial muscular dystrophy no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000713953 SCV001744916 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000154875 SCV001924228 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000713953 SCV001927038 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000713953 SCV001952059 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000713953 SCV001968772 likely benign not provided no assertion criteria provided clinical testing

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