Submissions for variant NM_001267550.2(TTN):c.47248G>A (p.Val15750Ile)

gnomAD frequency: 0.00202  dbSNP: rs72677232

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172668	SCV000051456	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040278	SCV000063969	likely benign	not specified	2015-01-26	criteria provided, single submitter	clinical testing	p.Val13182Ile in exon 201 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.3% (172/67614) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs72677232).
GeneDx	RCV000172668	SCV000237210	likely benign	not provided	2021-02-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17344846, 23396983, 24892279, 23861362)
Invitae	RCV001082393	SCV000262127	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251802	SCV000319558	likely benign	Cardiovascular phenotype	2018-12-14	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.
Eurofins Ntd Llc (ga)	RCV000172668	SCV000335872	uncertain significance	not provided	2015-09-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000262089	SCV000423146	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	RCV000331321	SCV000423147	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	RCV000385584	SCV000423148	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	RCV000296178	SCV000423149	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	RCV000332423	SCV000423150	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.
CeGaT Center for Human Genetics Tuebingen	RCV000172668	SCV000575281	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TTN: BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769009	SCV000900382	benign	Cardiomyopathy	2023-03-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000172668	SCV001146410	benign	not provided	2019-06-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172668	SCV001159342	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040278	SCV001821499	benign	not specified	2023-03-01	criteria provided, single submitter	clinical testing	Variant summary: TTN c.39544G>A (p.Val13182Ile) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 247926 control chromosomes, predominantly at a frequency of 0.0031 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 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although the variant, c.39544G>A, has been reported in the literature in individuals affected with hypertrophic cardiomyopathy, sudden unexplained death and various other phenotypes (e.g. Lopes_2013, Stewart_2014, Campuzano_2015, Ratnapriya_2020), no supporting evidence for causality was provided. 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. Eleven other ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic (n=1), uncertain significance (n=3), likely benign (n=5), and benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004534901	SCV004720271	likely benign	TTN-related disorder	2021-02-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Dr. Alfred Bastarche Laboratory, Dr. Georges L. Dumont University Hospital Centre	RCV000767391	SCV000840457	likely pathogenic	Limb-girdle muscular dystrophy	2018-10-18	no assertion criteria provided	clinical testing