Submissions for variant NM_001267550.2(TTN):c.103688T>C (p.Val34563Ala)

gnomAD frequency: 0.00061  dbSNP: rs55945684

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040931	SCV000064622	likely benign	not specified	2021-04-14	criteria provided, single submitter	clinical testing	The p.Val31995Ala variant in TTN is classified as likely benign because it has been identified in 0.08% (21/25012) of Finnish chromosomes and 0.07% (93/128166) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, this variant has been identified in at least 2 individuals that harbored other disease-causing variants in other cardiomyopathy associated genes (Campuzano 2014 PMID: 25447171, LMM data). ACMG/AMP Criteria applied: BS1, BP5.
GeneDx	RCV000040931	SCV000237916	likely benign	not specified	2017-06-01	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	RCV001083917	SCV000261429	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000245149	SCV000318898	likely benign	Cardiovascular phenotype	2020-07-24	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Eurofins Ntd Llc (ga)	RCV000725310	SCV000335950	uncertain significance	not provided	2015-10-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000361393	SCV000420145	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	RCV000264463	SCV000420146	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	RCV000322000	SCV000420147	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	RCV000263262	SCV000420149	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	RCV000316083	SCV000420150	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.
Athena Diagnostics	RCV000040931	SCV000615967	uncertain significance	not specified	2017-05-25	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000355491	SCV000995495	likely benign	Hypertrophic cardiomyopathy	2018-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725310	SCV001152587	uncertain significance	not provided	2018-09-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725310	SCV001473975	uncertain significance	not provided	2020-03-09	criteria provided, single submitter	clinical testing	The TTN c.103688T>C; p.Val34563Ala variant (rs55945684; ClinVar Variation ID: 47662) is reported in the literature in several individuals affected with HCM or DCM, though it was not demonstrated to cause disease (Franaszczyk 2017, Lopes 2013). This variant has been observed together with TTN variants p.Leu5742Phe and p.Glu33301Lys in the literature (Franaszczyk 2017, Lopes 2013) and in another individual tested at ARUP Laboratories. This suggests these three variants may occur in cis, although parental testing would be required to confirm this. This variant is rare in the population (<1% allele frequency in the Genome Aggregation Database) and 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.Val34563Ala 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). Franaszczyk M et al. Titin Truncating Variants in Dilated Cardiomyopathy - Prevalence and Genotype-Phenotype Correlations. PLoS One. 2017 Jan 3;12(1):e0169007. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798211	SCV002043117	benign	Cardiomyopathy	2022-08-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000725310	SCV002541905	uncertain significance	not provided	2021-12-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040931	SCV002599000	likely benign	not specified	2022-09-06	criteria provided, single submitter	clinical testing	Variant summary: TTN c.95984T>C (p.Val31995Ala) results in a non-conservative amino acid change located in the M-band of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 248956 control chromosomes. The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is benign. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=6, VUS n=7). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004534957	SCV004737722	uncertain significance	TTN-related disorder	2024-01-08	criteria provided, single submitter	clinical testing	The TTN c.103688T>C variant is predicted to result in the amino acid substitution p.Val34563Ala. This variant has been reported in an individual that suffered sudden cardiac death; however, the patient had variants of uncertain significance in TTN and MYH7 (reported as p.Val31995Ala in Campuzano et al. 2014. PubMed ID: 25447171). This variant is reported in 0.084% of alleles in individuals of European (Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.