Submissions for variant NM_001267550.2(TTN):c.33053G>A (p.Arg11018Gln)

gnomAD frequency: 0.00093  dbSNP: rs72650034

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000154080	SCV000055029	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040152	SCV000063843	likely benign	not specified	2015-03-12	criteria provided, single submitter	clinical testing	p.Arg9774Gln in exon 132 of TTN: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 4 primates (rhesus, crab-eating macaque, baboon, and green monkey) have a glutamine (Gln) at this position despite high nearby amino acid conservation. Ad ditional computational prediction tools do not suggest a high likelihood of impa ct to the protein. This variant has been identified in 0.1% (70/66710) of Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs72650034).
Eurofins Ntd Llc (ga)	RCV000154080	SCV000203723	uncertain significance	not provided	2017-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000154080	SCV000237091	benign	not provided	2018-05-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 24503780)
Invitae	RCV001085855	SCV000286585	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000241592	SCV000318594	uncertain significance	Cardiovascular phenotype	2013-05-07	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770062	SCV000901488	benign	Cardiomyopathy	2020-03-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000154080	SCV001146372	benign	not provided	2018-10-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001133885	SCV001293599	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	RCV001133886	SCV001293600	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 Laboratory Services, Illumina	RCV001133887	SCV001293601	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	RCV001133888	SCV001293602	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	RCV001133889	SCV001293603	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001133888	SCV001368873	likely benign	Tibial muscular dystrophy	2019-02-16	criteria provided, single submitter	clinical testing	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BP1,BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040152	SCV001448312	benign	not specified	2020-11-09	criteria provided, single submitter	clinical testing	Variant summary: TTN c.29321G>A (p.Arg9774Gln) results in a conservative amino acid change located in the I-band of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00081 in 248694 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 2 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 benign. Nine 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=7, VUS n=2). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000154080	SCV001962335	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	TTN: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV004541146	SCV004780627	likely benign	TTN-related disorder	2020-03-20	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).