Submissions for variant NM_001267550.2(TTN):c.84977G>A (p.Arg28326Gln)

gnomAD frequency: 0.00014  dbSNP: rs200843338

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040711	SCV000064402	uncertain significance	not specified	2012-03-16	criteria provided, single submitter	clinical testing	The Arg25758Gln variant (TTN) has been seen in 1/6622 European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS). The TTN gene is strongly associated with DCM based on the high prevalence of loss-of-function variants but the role of missense variants i s unclear. Arginine (Arg) at position 25758 is conserved in evolution, suggestin g that the change would impact the protein. Other computational analyses (bioche mical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide stro ng support for or against an impact to the protein. Additional information is ne eded to fully assess the clinical significance of this variant.
Ambry Genetics	RCV000247193	SCV000318761	uncertain significance	Cardiovascular phenotype	2013-07-31	criteria provided, single submitter	clinical testing	The p.R25758Q variant (also known as c.77273G>A) is located in coding exon 274 of the TTN gene. This alteration results from a G to A substitution at nucleotide position 77273. The arginine at codon 25758 is replaced by glutamine, an amino acid with highly similar properties.​​ This variant was previously reported in dbSNP asrs200843338. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately0.02% (2/12018), having been observed in 0.02% (2/8220) of European American alleles, and not observed in 3798 African American alleles studied. This variant was not reported in the 1000 Genomes Project. Based on protein sequence alignment, this amino acid position isis conserved through mammals, but is not conserved through all available vertebrate species. In addition, this alteration is predicted to be possibly damaging by PolyPhen analysis.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Illumina Laboratory Services, Illumina	RCV000335949	SCV000421178	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	RCV000391984	SCV000421179	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	RCV000305618	SCV000421180	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.
Illumina Laboratory Services, Illumina	RCV000341787	SCV000421181	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	RCV000406632	SCV000421182	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.
Invitae	RCV000477567	SCV000542359	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726282	SCV000701330	uncertain significance	not provided	2017-03-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000726282	SCV000729856	likely benign	not provided	2019-07-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25163546)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170551	SCV001333137	likely benign	Cardiomyopathy	2020-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000040711	SCV002072223	uncertain significance	not specified	2017-09-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726282	SCV003825500	uncertain significance	not provided	2021-02-04	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000726282	SCV001740320	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000726282	SCV001917537	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726282	SCV001970283	uncertain significance	not provided		no assertion criteria provided	clinical testing