ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.96235G>A (p.Asp32079Asn) (rs200540781)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000725268 SCV000237820 likely benign not provided 2021-06-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000219446 SCV000272810 uncertain significance not specified 2015-03-24 criteria provided, single submitter clinical testing The p.Asp29511Asn variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 12/66690 European chromosomes a nd 6/11544 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs200540781). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp29511Asn variant is uncertain.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725268 SCV000335505 uncertain significance not provided 2015-09-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000273519 SCV000420607 uncertain significance 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 Clinical Services Laboratory,Illumina RCV000334102 SCV000420608 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 Clinical Services Laboratory,Illumina RCV000388603 SCV000420609 uncertain significance Myopathy, early-onset, 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 Clinical Services Laboratory,Illumina RCV000316543 SCV000420611 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.
Illumina Clinical Services Laboratory,Illumina RCV000375971 SCV000420612 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.
Invitae RCV000464293 SCV000542406 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-04-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617391 SCV000736061 likely benign Cardiovascular phenotype 2019-09-25 criteria provided, single submitter clinical testing Insufficient evidence
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000725268 SCV001552760 uncertain significance not provided no assertion criteria provided clinical testing The TTN p.Asp23014Asn variant was not identified in the literature but was identified in dbSNP (ID: rs200540781), ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, EGL Genetic Diagnostics, Laboratory for Molecular Medicine and Invitae) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 51 of 280188 chromosomes at a frequency of 0.000182 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 15 of 35360 chromosomes (freq: 0.000424), Other in 2 of 7126 chromosomes (freq: 0.000281), European (non-Finnish) in 32 of 128056 chromosomes (freq: 0.00025) and African in 2 of 24182 chromosomes (freq: 0.000083), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Asp23014 residue has limited species conservation information and computational analyses (PolyPhen-2, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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