Submissions for variant NM_001267550.2(TTN):c.88720C>T (p.Arg29574Cys)

gnomAD frequency: 0.00029  dbSNP: rs200513274

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727677	SCV000237706	likely benign	not provided	2021-06-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26582918)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223660	SCV000272791	uncertain significance	not specified	2015-05-28	criteria provided, single submitter	clinical testing	The p.Arg27006Cys variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 16/66722 European chromosomes a nd 6/8590 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs200513274). Computational prediction tools a nd conservation analysis suggest that this variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, the clinical significance of the p.Arg27006Cys variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000404508	SCV000421033	uncertain significance	Dilated cardiomyopathy 1G	2018-01-12	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	RCV000307858	SCV000421034	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-12	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	RCV000396053	SCV000421036	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-12	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	RCV000301842	SCV000421037	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-12	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	RCV000359092	SCV000421038	benign	Tibial muscular dystrophy	2018-01-12	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.
Invitae	RCV000526235	SCV000643849	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727677	SCV000854990	uncertain significance	not provided	2018-07-23	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000727677	SCV001475046	likely benign	not provided	2020-06-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223660	SCV002500567	uncertain significance	not specified	2023-01-23	criteria provided, single submitter	clinical testing	Variant summary: TTN c.81016C>T (p.Arg27006Cys) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 248676 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00025 vs 0.00039), allowing no conclusion about variant significance. c.81016C>T has been reported in the literature in an individual with suspected sudden cardiac death (Hertz_2016). This report 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. Eight ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=5), likely benign (n=2) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002354516	SCV002660300	uncertain significance	Cardiovascular phenotype	2020-02-13	criteria provided, single submitter	clinical testing	The p.R20509C variant (also known as c.61525C>T), located in coding exon 159 of the TTN gene, results from a C to T substitution at nucleotide position 61525. The arginine at codon 20509 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000727677	SCV003821042	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917699	SCV004731706	uncertain significance	TTN-related condition	2023-12-09	criteria provided, single submitter	clinical testing	The TTN c.88720C>T variant is predicted to result in the amino acid substitution p.Arg29574Cys. This variant has been reported in an individual with a cardiac phenotype who was also positive for a second missense variant in TTN (Case 32, Table S1, Hertz et al. 2015. PubMed ID: 26383259). This variant is reported in 0.041% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GenomeConnect, ClinGen	RCV000509283	SCV000607145	not provided	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Hypertrophic cardiomyopathy 9		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.