Submissions for variant NM_001267550.2(TTN):c.22386T>A (p.Asp7462Glu)

gnomAD frequency: 0.00004  dbSNP: rs183482849

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039969	SCV000063660	uncertain significance	not specified	2014-11-11	criteria provided, single submitter	clinical testing	The p.Asp6218Glu (c.18654T>A) variant in TTN has been identified by our laborato ry in 1 adult with DCM who also carries a pathogenic variant in TTN. In addition , this variant has been identified in 1/8218 European American chromosomes by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) and in 1/12 8 Mexican chromosomes by the 1000 Genomes Project (dbSNP rs183482849). Computati onal prediction tools and conservation analysis do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the p.Asp6218Glu variant is uncertain.
GeneDx	RCV001507605	SCV000238315	likely benign	not provided	2018-08-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24503780)
Invitae	RCV001065236	SCV001230186	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2019-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with glutamic acid at codon 7462 of the TTN protein (p.Asp7462Glu). There is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs183482849, ExAC 0.02%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 46699). This variant is located in the I band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001130565	SCV001290146	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	RCV001130566	SCV001290147	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	RCV001130567	SCV001290148	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	RCV001130568	SCV001290149	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	RCV001130569	SCV001290150	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507605	SCV001713247	uncertain significance	not provided	2019-07-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039969	SCV002014884	uncertain significance	not specified	2021-10-11	criteria provided, single submitter	clinical testing	Variant summary: TTN c.18654T>A (p.Asp6218Glu) results in a conservative amino acid change located in the I-band domain of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248042 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00012 vs 0.00039), allowing no conclusion about variant significance. c.18654T>A has been reported in the literature in individuals affected with Cardiomyopathy, without strong evidence for causality (ie. Kostareva_2016, Mucheu_2020). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; two classified as benign/likely benign while three classified as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV001507605	SCV003818532	uncertain significance	not provided	2022-06-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149640	SCV003838656	uncertain significance	Cardiomyopathy	2021-10-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415778	SCV004114823	uncertain significance	TTN-related condition	2023-06-29	criteria provided, single submitter	clinical testing	The TTN c.22386T>A variant is predicted to result in the amino acid substitution p.Asp7462Glu. This variant was reported in individuals with restrictive cardiomyopathy or hypertrophic cardiomyopathy; however, no additional studies were performed to help assess the pathogenicity of this variant (Table S3, Kostareva et al. 2016. PubMed ID: 27662471; Micheu et al. 2020. PubMed ID: 33297573). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179587128-A-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/46699). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001507605	SCV001797829	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001507605	SCV001809435	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001507605	SCV001923067	uncertain significance	not provided		no assertion criteria provided	clinical testing