Submissions for variant NM_001267550.2(TTN):c.104576G>A (p.Arg34859Gln) (rs68080670)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000040944	SCV000051758	benign	not specified	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000040944	SCV000064635	benign	not specified	2012-04-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000040944	SCV000169471	benign	not specified	2017-02-22	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	RCV000231098	SCV000286405	benign	Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J	2019-12-31	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000040944	SCV000315643	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000244925	SCV000318088	benign	Cardiovascular phenotype	2019-02-07	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000402951	SCV000420074	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.
Illumina Clinical Services Laboratory,Illumina	RCV000296735	SCV000420075	likely benign	Myopathy, early-onset, 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 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 Clinical Services Laboratory,Illumina	RCV000351463	SCV000420076	likely benign	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 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 Clinical Services Laboratory,Illumina	RCV000403378	SCV000420077	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 Clinical Services Laboratory,Illumina	RCV000677191	SCV000420078	likely benign	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 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.
Integrated Genetics/Laboratory Corporation of America	RCV000040944	SCV001338573	benign	not specified	2020-04-06	criteria provided, single submitter	clinical testing	Variant summary: TTN c.96872G>A (p.Arg32291Gln) results in a conservative amino acid change located in the M-band region (cardiodb.org) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.013 in 248790 control chromosomes in the gnomAD database, including 37 homozygotes. The observed variant frequency is approximately 20-fold the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.96872G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant with conflicting assessments (benign, n=3; likely benign, n=1; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory,University of Chicago	RCV000040944	SCV000153434	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000677191	SCV000803296	likely pathogenic	Limb-girdle muscular dystrophy, type 2J	2018-07-18	no assertion criteria provided	clinical testing	The observed variant c.104576G>A (p.Arg34859Gln) has a minor allele frequency of 0.0036 and 0.0130 in 1000 Genomes and ExAC databases respectively. The in silico prediction of the given variant is disease causing by MutationTaster2, and damaging by SIFT.