Submissions for variant NM_001267550.2(TTN):c.59729C>T (p.Thr19910Ile)

gnomAD frequency: 0.00010  dbSNP: rs369476725

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154934	SCV000204616	uncertain significance	not specified	2017-06-28	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Thr17342Ile v ariant in TTN has previously been identified by our laboratory in one Caucasian individual with DCM, who also carried a likely pathogenic variant sufficient to explain their disease. This variant has also been identified in 0.18% (18/9784) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs369476725). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. In sum mary, while the clinical significance of the Thr17342Ile variant is uncertain, i ts frequency suggests that it is more likely to be benign.
Athena Diagnostics Inc	RCV000154934	SCV000616114	uncertain significance	not specified	2017-02-10	criteria provided, single submitter	clinical testing
Invitae	RCV000643026	SCV000764713	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-08-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765564	SCV000896879	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000786261	SCV000978012	likely benign	not provided	2021-04-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001129407	SCV001288930	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	RCV001129408	SCV001288931	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001129409	SCV001288932	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	RCV001129410	SCV001288933	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	RCV001129411	SCV001288934	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.
Revvity Omics, Revvity	RCV000786261	SCV003826727	uncertain significance	not provided	2019-07-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000786261	SCV004152355	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	TTN: PM2
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786261	SCV000925012	uncertain significance	not provided	2017-10-16	no assertion criteria provided	provider interpretation	p.Thr17342Ile (c.52025C>T) in exon 251 of the TTN gene (NM_133378.4; Chr2g.179456902G>A). SCICD Classification: variant of uncertain significance, likely benign based on relatively high frequency in the general population, lack of case data and failure to segregate with disease . We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: TTN: TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN truncating variants are seen in 13-30% of people with DCM and are thought to confer pathogenesis in a dominant-negative fashion (Herman et al 2012, Roberts et al 2015). There is strong evidence implicating them in the pathogenesis of DCM, though it remains unclear whether they are confer risk in a Mendelian or multifactorial fashion (Watkins et al 2015). Furthermore, each individual TTN variant must be evaluated carefully for potential pathogenicity given the presence of truncating TTN variants in 1-3% of the general population (Herman et al 2012, Roberts et al 2015) and the failure of some TTN truncating variants to segregate in DCM families (Norton et al 2013). Case data (not including our patient): ClinVar: present in 1 lab: Laboratory for Molecular Medicine: 1 patient with DCM who had a pathogenic variant in another gene. Cases in the literature: none reported. Segregation data: none reported. Functional data: none reported. In silico data (missense variants only): Per the test report, "Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. " Conservation data: The threonine at codon 17342 is almost completely conserved across species. Neighboring amino acids are similarly conserved. Nearby pathogenic variants at this codon or neighboring codons: none. Population data: Highest MAF in Ashkenazi Jewish population: 0.18%. The variant was reported online in 33 of 121,946 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 18 of 4,892 individuals of Ashkenazi Jewish descent (MAF=0.18%), 9 of 55,151 individuals of European descent, 2 of 16,689 individuals of Latino descent, 1 of 15,341 individuals of South Asian descent and 3 of 2,703 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.