Submissions for variant NM_001267550.2(TTN):c.61289G>A (p.Cys20430Tyr)

gnomAD frequency: 0.00005  dbSNP: rs527704660

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152267	SCV000201111	uncertain significance	not specified	2013-10-21	criteria provided, single submitter	clinical testing	The Cys17862Tyr variant in TTN has not been reported in individuals with cardiom yopathy. Computational analyses (biochemical amino acid properties, conservation , AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of t his variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535645	SCV000643469	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000714063	SCV000844729	uncertain significance	not provided	2018-01-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001128975	SCV001288471	uncertain significance	Tibial muscular dystrophy	2018-01-15	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	RCV001128976	SCV001288472	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-15	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	RCV001128977	SCV001288473	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-15	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	RCV001128978	SCV001288474	uncertain significance	Dilated cardiomyopathy 1G	2018-01-15	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	RCV001128979	SCV001288475	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-15	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	RCV000714063	SCV001825023	likely benign	not provided	2019-05-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30993396)
Ambry Genetics	RCV002453496	SCV002614357	uncertain significance	Cardiovascular phenotype	2019-03-11	criteria provided, single submitter	clinical testing	The p.C11365Y variant (also known as c.34094G>A), located in coding exon 131 of the TTN gene, results from a G to A substitution at nucleotide position 34094. The cysteine at codon 11365 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152267	SCV003934127	uncertain significance	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.53585G>A (p.Cys17862Tyr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-05 in 247286 control chromosomes, predominantly at a frequency of 0.00056 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant may be a benign polymorphism found primarily in populations of East Asian origin. c.53585G>A has been reported in the literature as a compound heterozygous genotype in an individual of Chinese ancestry affected with Dilated Cardiomyopathy (Dai_2019) and in the heterozygous state in a Korean survivor of a sudden cardiac arrest who also harbored a pathogenic variant in RYR2 (Song_2017). 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. The following publications have been ascertained in the context of this evaluation (PMID: 30993396, 28202948). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000714063	SCV004225846	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486676	SCV004239973	benign	Cardiomyopathy	2022-10-03	criteria provided, single submitter	clinical testing