Submissions for variant NM_001267550.2(TTN):c.80983G>A (p.Glu26995Lys)

gnomAD frequency: 0.00010  dbSNP: rs397517719

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040663	SCV000064354	uncertain significance	not specified	2013-07-05	criteria provided, single submitter	clinical testing	The Glu24427Lys variant in TTN has been identified by our laboratory in 1 Caucas ian individual with DCM (LMM unpublished data) and was not identified in large p opulation studies. Glutamic acid (Glu) at position 24427 is not well conserved i n evolution and 1 species (zebra finch) carries a lysine (Lys; this variant) at this position, raising the possibility that this change may be tolerated. Other computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen, and SIFT) do not provide strong support for or against an impact to the protein. At this time, additional information is needed to fully assess the clinical sig nificance of this variant.
GeneDx	RCV000726121	SCV000237607	likely benign	not provided	2021-03-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24503780)
Eurofins Ntd Llc (ga)	RCV000726121	SCV000342142	uncertain significance	not provided	2016-08-25	criteria provided, single submitter	clinical testing
Invitae	RCV001079917	SCV000643741	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617992	SCV000737292	uncertain significance	Cardiovascular phenotype	2017-07-12	criteria provided, single submitter	clinical testing	The p.E17930K variant (also known as c.53788G>A), located in coding exon 153 of the TTN gene, results from a G to A substitution at nucleotide position 53788. The glutamic acid at codon 17930 is replaced by lysine, an amino acid with similar properties. This alteration was reported in an individual with features of dilated cardiomyopathy (DCM) who also had additional alterations in TTN and other cardiac-related genes (Pugh TJ et al. Genet. Med. 2014;16:601-8). This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000726121	SCV001160503	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	The TTN c.80983G>A; p.Glu26995Lys variant (rs397517719; ClinVar Variation ID: 47393) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has been reported in one individual with dilated cardiomyopathy (DCM) (Pugh 2014). The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Glu26995Lys variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. Pugh TJ et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014 Aug;16(8):601-8. PMID: 24503780.
Illumina Laboratory Services, Illumina	RCV001132747	SCV001292418	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	RCV001132748	SCV001292419	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	RCV001132749	SCV001292420	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	RCV001136159	SCV001295981	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	RCV001136160	SCV001295982	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798182	SCV002043001	benign	Cardiomyopathy	2021-05-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726121	SCV003824744	uncertain significance	not provided	2022-08-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000726121	SCV004225806	uncertain significance	not provided	2022-10-07	criteria provided, single submitter	clinical testing	BP4