Submissions for variant NM_001267550.2(TTN):c.54178G>A (p.Val18060Ile)

gnomAD frequency: 0.00005  dbSNP: rs190574498

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152310	SCV000201187	uncertain significance	not specified	2013-12-11	criteria provided, single submitter	clinical testing	The Val15492Ile variant in TTN has not been reported in individuals with cardiom yopathy, but has been identified in 1/8270 European American chromosomes by the NHLBI Exome Sequencing Project and in 1/192 Kenyan chromosomes by the 1000 genom es project (http://evs.gs.washington.edu/EVS/; dbSNP rs190574498). Valine (Val) at position 15492 is generally conserved in evolution; however, the change to is oleucine (Ile) is present in one mammalian species (naked mole rat). Additional computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein . Additional information is needed to fully assess the clinical significance of the Val15492Ile variant.
Invitae	RCV000532070	SCV000643357	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-02-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000730160	SCV000857875	uncertain significance	not provided	2017-11-07	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852518	SCV000995216	uncertain significance	Ventricular tachycardia	2018-04-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001129095	SCV001288593	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	RCV001129096	SCV001288594	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	RCV001129097	SCV001288595	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	RCV001129098	SCV001288596	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	RCV001129099	SCV001288597	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.
GeneDx	RCV000730160	SCV001745724	likely benign	not provided	2020-10-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426723	SCV002743457	uncertain significance	Cardiovascular phenotype	2018-11-15	criteria provided, single submitter	clinical testing	The p.V8995I variant (also known as c.26983G>A), located in coding exon 107 of the TTN gene, results from a G to A substitution at nucleotide position 26983. The valine at codon 8995 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be benign by PolyPhen in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000730160	SCV003824923	uncertain significance	not provided	2019-09-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000730160	SCV004042101	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	TTN: BP4
PreventionGenetics, part of Exact Sciences	RCV003415994	SCV004114742	uncertain significance	TTN-related condition	2022-12-27	criteria provided, single submitter	clinical testing	The TTN c.54178G>A variant is predicted to result in the amino acid substitution p.Val18060Ile. This variant was reported in an individual from a large cohort of patients with dilated cardiomyopathy; however no additional evidence was provided to indicate causation (Burstein et al. 2021. PubMed ID: 32746448, Supplemental Table 2). This variant is reported in 0.017% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179469726-C-T). In ClinVar, it has been classified as uncertain, likely benign, and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/165977/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486678	SCV004239947	likely benign	Cardiomyopathy	2022-08-02	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000730160	SCV001978163	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000730160	SCV001980004	likely benign	not provided		no assertion criteria provided	clinical testing