Submissions for variant NM_001267550.2(TTN):c.26672A>G (p.Asn8891Ser)

gnomAD frequency: 0.00025  dbSNP: rs146057575

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040055	SCV000063746	benign	not specified	2013-04-17	criteria provided, single submitter	clinical testing	Asn7647Ser in exon 89 of TTN: This variant is not expected to have clinical sign ificance because it has been identified in 3.1% (6/192) of Luhya chromosomes by the 1000 Genomes Project (dbSNP rs146057575). In addition, multiple mammals (inc luding bushbaby, rat, hedgehog, and elephant) carry a serine (Ser) at this posit ion.
GeneDx	RCV000488131	SCV000238379	likely benign	not provided	2021-06-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24503780, 24781210, 28771489)
Eurofins Ntd Llc (ga)	RCV000040055	SCV000336986	likely benign	not specified	2016-03-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000333598	SCV000423980	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	RCV000381135	SCV000423981	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	RCV000289133	SCV000423982	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	RCV000327811	SCV000423983	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.
Illumina Laboratory Services, Illumina	RCV000284411	SCV000423985	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.
CeGaT Center for Human Genetics Tuebingen	RCV000488131	SCV000575287	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	TTN: BP4, BS2
Athena Diagnostics	RCV000488131	SCV000616039	likely benign	not provided	2018-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084221	SCV000642889	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-27	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000327811	SCV001366433	likely benign	Tibial muscular dystrophy	2019-02-14	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,BP6.
Mayo Clinic Laboratories, Mayo Clinic	RCV000488131	SCV001713240	uncertain significance	not provided	2021-10-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040055	SCV002571010	likely benign	not specified	2022-07-25	criteria provided, single submitter	clinical testing	Variant summary: TTN c.22940A>G (p.Asn7647Ser) results in a conservative amino acid change located in the I band of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 248780 control chromosomes, predominantly at a frequency of 0.0007 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database 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 a benign polymorphism found primarily in populations of Latino origin. c.22940A>G has been reported in the literature in individuals who have been screened for cardiomyopathy associated genes (examples: Pugh_2014, Michaud_2014, Campuzano_2015, Mademont-Soler_2017, and Martnez-Barrios_2022). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=1), likely benign (n=5) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000488131	SCV001742781	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000488131	SCV001917148	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000488131	SCV001931163	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000488131	SCV001968367	likely benign	not provided		no assertion criteria provided	clinical testing