ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.43690T>A (p.Ser14564Thr) (rs181189778)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040242 SCV000063933 likely benign not specified 2018-10-10 criteria provided, single submitter clinical testing The p.Ser11996Thr variant in TTN is classified as likely benign because it has b een identified in 0.07% (22/33594) of Latino chromosomes and 0.04% (50/121836) o f European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Cr iteria applied: BS1.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725048 SCV000333513 uncertain significance not provided 2015-07-28 criteria provided, single submitter clinical testing
Invitae RCV000463518 SCV000542274 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000725048 SCV000605504 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing The TTN c.35986T>A; p.Ser11996Thr variant (rs181189778, ClinVar variant ID 46972) has been identified in a case of sudden infant death, together with one additional TTN variant, p.Thr21743Ala, and five other variants in VCL, KCNE3, PKP2, EN1 and AKAP9 genes (Campuzano 2014). An unaffected mother and sister also carried the p.Ser11996Thr variant, and the authors concluded that the reported variants in TTN gene were not responsible for the proband’s death (Campuzano 2014). This variant is rare in the general population (<1% allele frequency in the Genome Aggregation Database). . The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. While the clinical significance of such variants is considered uncertain, evidence suggests that the vast majority of missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Given the available evidence, the clinical significance of the p.Ser11996Thr variant cannot be determined with certainty.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852859 SCV000995593 likely benign Arrhythmogenic right ventricular cardiomyopathy 2019-02-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001130917 SCV001290512 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). 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 Clinical Services Laboratory,Illumina RCV001130918 SCV001290513 uncertain significance 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 Clinical Services Laboratory,Illumina RCV001130919 SCV001290514 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). 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 Clinical Services Laboratory,Illumina RCV001130920 SCV001290515 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.
Illumina Clinical Services Laboratory,Illumina RCV001130921 SCV001290516 uncertain significance Myopathy, early-onset, 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171013 SCV001333682 likely benign Cardiomyopathy 2018-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040242 SCV001363994 likely benign not specified 2019-10-30 criteria provided, single submitter clinical testing Variant summary: TTN c.35986T>A (p.Ser11996Thr) results in a conservative amino acid change in the I-band region of the 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 0.0003 in 239664 control chromosomes, predominantly at a frequency of 0.00068 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.35986T>A has been reported in the literature in association with sudden infant death syndrome (SIDS) and sudden arrhythmic death syndrome (SADS) without strong evidence of causality (Campuzano_2014, Nunn_2016). In the one SIDS case the variant was also detected in unaffected family members with the authors concluding that it is not responsible for the death of the index case (Campuzano_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=2) and as uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

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