Submissions for variant NM_001267550.2(TTN):c.87623A>T (p.Tyr29208Phe)

gnomAD frequency: 0.00020  dbSNP: rs201831707

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040734	SCV000064425	uncertain significance	not specified	2012-01-10	criteria provided, single submitter	clinical testing	The Tyr26640Phe variant (TTN) has not been reported in the literature, but has b een identified in 5/6690 European American chromosomes and 1/3224 African Americ an chromosomes from a broad, though clinically unspecified population (NHLBI Exo me Sequencing Project; http://evs.gs.washington.edu/EVS). Tyrosine (Tyr) at posi tion 26640 is highly conserved in mammals and across evolutionarily distant spec ies, increasing the likelihood that a change would not be tolerated. Computation al predictions on the impact to the protein are mixed (AlignGVGD, SIFT), though the accuracy of these tools is unknown. Additional data is needed to further ass ess the clinical significance of the Tyr26640Phe variant.
GeneDx	RCV000040734	SCV000237683	likely benign	not specified	2018-01-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000225888	SCV000286887	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-07-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000244493	SCV000318374	uncertain significance	Cardiovascular phenotype	2013-03-18	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Eurofins Ntd Llc (ga)	RCV000726191	SCV000701287	uncertain significance	not provided	2017-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001129285	SCV001288801	uncertain significance	Dilated cardiomyopathy 1G	2018-01-19	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	RCV001136271	SCV001296100	benign	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 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	RCV001136272	SCV001296101	benign	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 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	RCV001136273	SCV001296102	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-19	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	RCV001136274	SCV001296103	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-19	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	RCV000040734	SCV001821437	uncertain significance	not specified	2021-08-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.79919A>T (p.Tyr26640Phe) results in a 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 0.0002 in 280402 control chromosomes, predominantly at a frequency of 0.00038 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is somewhat lower than the maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), allowing no conclusion about variant significance. However, the variant is observed in North-western European subpopulation with an even higher frequency, 0.0006338, suggesting that the variant could be benign. c.79919A>T has been reported in the literature in 2 individuals affected with Dilated Cardiomyopathy (Pugh_2014, Haskell_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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798190	SCV002043033	likely benign	Cardiomyopathy	2021-03-26	criteria provided, single submitter	clinical testing