Submissions for variant NM_001267550.2(TTN):c.33416G>C (p.Arg11139Thr)

gnomAD frequency: 0.00146  dbSNP: rs72650040

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172680	SCV000055027	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040158	SCV000063849	likely benign	not specified	2012-04-25	criteria provided, single submitter	clinical testing	Arg9895Thr in exon 140 of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (28/6630) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/rs72650040). Arg9895Thr in exon 140 of TTN (rs72650040; allele frequency = 0.4%, 28/6630) **
GeneDx	RCV000172680	SCV000237096	benign	not provided	2019-09-03	criteria provided, single submitter	clinical testing
Invitae	RCV001082271	SCV000261628	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000040158	SCV000315472	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000040158	SCV000337324	likely benign	not specified	2016-08-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770057	SCV000901483	benign	Cardiomyopathy	2023-01-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172680	SCV001152977	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TTN: BP4
Illumina Laboratory Services, Illumina	RCV001130090	SCV001289653	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	RCV001130091	SCV001289654	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	RCV001130092	SCV001289655	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	RCV001135119	SCV001294889	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	RCV001135120	SCV001294890	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040158	SCV001748735	likely benign	not specified	2021-07-06	criteria provided, single submitter	clinical testing	Variant summary: TTN c.29684G>C (p.Arg9895Thr) results in a non-conservative amino acid change located in the I-band (https://www.cardiodb.org) of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0016 in 248220 control chromosomes, predominantly at a frequency of 0.0026 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 6.7 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. c.29684G>C has been reported in the literature in individuals without strong evidence for pathogenicity (Campuzano_2015). This report therefore, does 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. Seven ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=5) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.