Submissions for variant NM_001267550.2(TTN):c.49413G>T (p.Trp16471Cys)

gnomAD frequency: 0.00042  dbSNP: rs202094100

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040300	SCV000063991	likely benign	not specified	2023-06-26	criteria provided, single submitter	clinical testing	The p.Trp13903Cys variant in TTN is classified as likely benign because it has been identified in 0.07% (47/67932) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). ACMG/AMP Criteria applied: BS1.
GeneDx	RCV000184581	SCV000237249	likely benign	not provided	2021-05-17	criteria provided, single submitter	clinical testing	Reported previously, as W13903C in an alternate transcript, as a variant of uncertain significance in a child with dilated cardiomyopathy who had multiple other variants in different genes (Pugh et al., 2014); Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 30847666)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000184581	SCV000281414	uncertain significance	not provided	2016-04-08	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Ambry Genetics	RCV000248683	SCV000318684	uncertain significance	Cardiovascular phenotype	2013-05-26	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Illumina Laboratory Services, Illumina	RCV000357355	SCV000423019	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	RCV000317820	SCV000423021	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	RCV000372520	SCV000423022	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	RCV000275689	SCV000423023	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.
Illumina Laboratory Services, Illumina	RCV000330719	SCV000423024	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.
Invitae	RCV000560033	SCV000643276	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000184581	SCV000701050	uncertain significance	not provided	2018-06-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764335	SCV000895354	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000184581	SCV001152893	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TTN: PM2:Supporting, PP3, BP1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170837	SCV001333457	benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000184581	SCV001715766	uncertain significance	not provided	2021-09-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040300	SCV002050818	likely benign	not specified	2023-07-05	criteria provided, single submitter	clinical testing	Variant summary: TTN c.41709G>T (p.Trp13903Cys) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 278566 control chromosomes (gnomAD), predominantly at a frequency of 0.00065 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 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.41709G>T has been reported in the literature in individuals affected with Hypertrophic and Dilated Cardiomyopathy (e.g. Pugh_2014, Campuzano_2015, Huang_2016, Mademont-Soler_2017, van Lint_2019) and Preeclampsia (Gammill_2018). These data indicate that the variant may potentially be associated with disease, however Co-occurrence with a pathogenic variant has been reported within our lab (MYH7 c.1447G>A/p.E483K), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 30021846, 25825243, 31395899, 28771489, 24503780, 30847666). Twelve ClinVar submitters have assessed the variant since 2014: eight classified the variant as uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000184581	SCV003820306	uncertain significance	not provided	2021-10-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534902	SCV004114414	uncertain significance	TTN-related disorder	2023-06-15	criteria provided, single submitter	clinical testing	The TTN c.49413G>T variant is predicted to result in the amino acid substitution p.Trp16471Cys. This variant (also described as p.Trp13903Cys) has been reported in patients with hypertrophic, dilated or arrhythmogenic right ventricular cardiomyopathy, although pathogenicity was clearly established (Supplementary File 2, van Lint. 2019. PubMed ID: 30847666; Table S1, Pugh. 2014. PubMed ID: 24503780; Table S1, Campuzano. 2015. PubMed ID: 26516846; Table S2, Mademont-Soler. 2017. PubMed ID: 28771489). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179478597-C-A). This variant is reported in ClinVar with conflicting interpretations of uncertain, likely benign and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/47030/) At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.