ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.35264A>C (p.Lys11755Thr)

gnomAD frequency: 0.00172  dbSNP: rs189966800
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000040184 SCV000051434 benign not specified 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000040184 SCV000063875 benign not specified 2017-11-13 criteria provided, single submitter clinical testing p.Lys10454Thr in exon 151 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.6% (142/22990) of African chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs189966800). BA1
Eurofins Ntd Llc (ga) RCV000040184 SCV000226379 benign not specified 2014-12-16 criteria provided, single submitter clinical testing
GeneDx RCV001719766 SCV000237118 likely benign not provided 2020-12-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23861362)
Ambry Genetics RCV000246293 SCV000318941 likely benign Cardiovascular phenotype 2013-11-08 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.
Illumina Laboratory Services, Illumina RCV000389983 SCV000423535 uncertain significance Early-onset myopathy with fatal cardiomyopathy 2018-01-13 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 RCV000364890 SCV000423537 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-01-13 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 RCV000274824 SCV000423538 benign Myopathy, myofibrillar, 9, with early respiratory failure 2018-01-13 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 RCV000329904 SCV000423539 uncertain significance Dilated cardiomyopathy 1G 2018-01-13 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 RCV000370805 SCV000423540 benign Tibial muscular dystrophy 2018-01-13 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 RCV000464829 SCV000555235 benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-28 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769035 SCV000900408 likely benign Cardiomyopathy 2016-09-08 criteria provided, single submitter clinical testing
Genetics and Genomics Program, Sidra Medicine RCV001293076 SCV001434059 likely benign Primary dilated cardiomyopathy criteria provided, single submitter research
Athena Diagnostics RCV000040184 SCV001477128 benign not specified 2019-11-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040184 SCV001774445 benign not specified 2021-07-19 criteria provided, single submitter clinical testing Variant summary: TTN c.31361A>C (p.Lys10454Thr) results in a non-conservative amino acid change located in the I-band region 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 0.00044 in 238212 control chromosomes, predominantly at a frequency of 0.0062 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 16-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.31361A>C 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 benign/likely benign and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001719766 SCV004564703 likely benign not provided 2023-03-28 criteria provided, single submitter clinical testing
Clinical Genetics, Academic Medical Center RCV000040184 SCV001978969 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001719766 SCV001979987 likely benign not provided no assertion criteria provided clinical testing

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