Submissions for variant NM_001267550.2(TTN):c.63352C>T (p.Arg21118Trp)

gnomAD frequency: 0.00020  dbSNP: rs200726948

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172292	SCV000054965	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040464	SCV000064155	uncertain significance	not specified	2012-10-24	criteria provided, single submitter	clinical testing	The Arg18550Trp variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 1/569 ch romosomes from the ClinSeq project listed in dbSNP (rs200726948). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg18550Trp variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. Additional studies are needed to fully assess its clinical significance.
Ambry Genetics	RCV000248255	SCV000319102	uncertain significance	Cardiovascular phenotype	2013-11-11	criteria provided, single submitter	clinical testing	The p.R18550W variant (also known as c.55648C>T) is located in coding exon 253 of the TTN gene. This alteration results from a C to T substitution at nucleotide position 55648. The arginine at codon 18550 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was identified in 1/930 alleles (1/465 individuals) in a subset of the ClinSeq cohort that was reported in a recent publication, and authors classified this as a variant of unknown significance (Ng et al.Circ Cardiovasc Genet. 2013;6:337-346).This variant was previously reported in dbSNP asrs200726948.This variant was not reported in population-based cohorts in the 1000 Genomes Project or the NHLBI Exome Sequencing Project (ESP). In the ESP, this variant was not reported in 6145 samples (12290 alleles) with coverage at this position.Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species.In addition, this alteration is predicted to be probably damaging by PolyPhen in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Illumina Laboratory Services, Illumina	RCV000367338	SCV000422395	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	RCV000332764	SCV000422397	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	RCV000382596	SCV000422398	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	RCV000269467	SCV000422399	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	RCV000328753	SCV000422400	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	RCV001080206	SCV000643503	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000172292	SCV000979305	likely benign	not provided	2020-11-24	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852826	SCV000995555	likely benign	Cardiomyopathy	2018-09-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172292	SCV001152820	uncertain significance	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000172292	SCV003819677	uncertain significance	not provided	2020-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040464	SCV004020343	likely benign	not specified	2023-06-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.55648C>T (p.Arg18550Trp) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 247928 control chromosomes, predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3.071 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.55648C>T has been reported in the literature in at least one individual affected with Ventricular tachycardia without evidence of causality (example: Guelly_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33552729). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=3), likely benign (n=3), or benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.