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

gnomAD frequency: 0.00031  dbSNP: rs181189778

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
Eurofins Ntd Llc (ga)	RCV000725048	SCV000333513	uncertain significance	not provided	2015-07-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463518	SCV000542274	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive 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 Laboratory Services, 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 Laboratory Services, Illumina	RCV001130918	SCV001290513	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). 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, Illumina	RCV001130921	SCV001290516	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). 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	2020-07-08	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.
GeneDx	RCV000725048	SCV001814446	likely benign	not provided	2020-07-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28771489, 25016126)
Ambry Genetics	RCV002399389	SCV002705527	likely benign	Cardiovascular phenotype	2019-10-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Revvity Omics, Revvity	RCV000725048	SCV003826740	uncertain significance	not provided	2022-08-29	criteria provided, single submitter	clinical testing