Submissions for variant NM_001267550.2(TTN):c.83516G>A (p.Arg27839Gln)

gnomAD frequency: 0.00042  dbSNP: rs376820301

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487528	SCV000237647	likely benign	not provided	2020-09-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26559152, 25163546, 24440382, 30993396, 33692775)
Invitae	RCV001081800	SCV000286867	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000242513	SCV000318050	uncertain significance	Cardiovascular phenotype	2013-01-29	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Eurofins Ntd Llc (ga)	RCV000487528	SCV000333174	uncertain significance	not provided	2015-07-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000366970	SCV000421267	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.
Illumina Laboratory Services, Illumina	RCV000274523	SCV000421268	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	RCV000299241	SCV000421269	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	RCV000259353	SCV000421271	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	RCV000317203	SCV000421272	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.
CeGaT Center for Human Genetics Tuebingen	RCV000487528	SCV000575274	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TTN: PM2, BP4
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000356458	SCV000995531	likely benign	Hypertrophic cardiomyopathy	2018-12-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000259119	SCV001337743	likely benign	not specified	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: TTN c.75812G>A (p.Arg25271Gln) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 245148 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.76 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.75812G>A has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Haas_2015) and Hirschsprung Disease (e.g. Luzon-Toro_2015) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least one publication reports experimental evidence finding an impact of the variant on thermal stability (Rees_2023), however, this does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 25163546, 24440382, 30993396, 26559152, 33692775, 37549721). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=2), likely benign (n=3), or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798632	SCV002043012	benign	Cardiomyopathy	2020-05-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528940	SCV004108956	uncertain significance	TTN-related disorder	2023-09-10	criteria provided, single submitter	clinical testing	The TTN c.83516G>A variant is predicted to result in the amino acid substitution p.Arg27839Gln. This variant was reported in individuals with dilated cardiomyopathy (described as p.Arg18966Gln in Table S6, Haas et al. 2015. PubMed ID: 25163546; Stoiber et al. 2020. PubMed ID: 33692775). It was also identified in two affected individuals with Hirschsprung disease from one family (Table S2, Luzón-Toro et al. 2015. PubMed ID: 26559152). However, it was also found in controls in a dilated cardiomyopathy case-control study (Table S8, Dai et al. 2019. PubMed ID: 30993396). This variant is reported in 0.11% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179427343-C-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/196060). 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.