Submissions for variant NM_001267550.2(TTN):c.102271C>T (p.Arg34091Trp)

gnomAD frequency: 0.00095  dbSNP: rs140319117

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154875	SCV000204557	likely benign	not specified	2017-06-05	criteria provided, single submitter	clinical testing	p.Arg31523Trp in exon 307 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.3% (33/10126) of Ashkenazi Jewi sh chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org/; dbSNP rs140319117).
Eurofins Ntd Llc (ga)	RCV000713953	SCV000229375	uncertain significance	not provided	2018-09-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000713953	SCV000236911	likely benign	not provided	2020-08-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24055113, 24231549, 15802564, 24569025, 23514108, 23446887, 24625729, 26272908, 23486992, 24271327, 24578547, 28009443, 28256728, 27194543, 23861362, 33232181)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086721	SCV000555083	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621822	SCV000735076	likely benign	Cardiovascular phenotype	2019-11-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Athena Diagnostics	RCV000154875	SCV000844602	benign	not specified	2020-06-29	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852776	SCV000995499	likely benign	Primary dilated cardiomyopathy; Heart failure	2018-07-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001134221	SCV001293954	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000119019	SCV001293955	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001134222	SCV001293956	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000509179	SCV001293957	benign	Tibial muscular dystrophy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001134223	SCV001293958	uncertain significance	Dilated cardiomyopathy 1G	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154875	SCV001748673	likely benign	not specified	2021-06-21	criteria provided, single submitter	clinical testing	Variant summary: TTN c.94567C>T (p.Arg31523Trp) results in a non-conservative amino acid change located in the M-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 0.0011 in 247286 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.84 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 Non-Finnish European origin. c.94567C>T was initially reported to segregate with disease in two families with hereditary myopathy with early respiratory failure (HMERF; Lange_2005). However, subsequent reports have reported a missense mutation in the fibronectin-like FN3 119 domain of A-band titin in several Swedish families with HMERF (Ohlsson et al., 2012) including the patients reported in Lange_2005, which suggests the second mutation as the likely candidate for pathogenicity in the two initial families reported (Hedberg_2014). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Lange_2005). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six labs classified the variant as likely benign/benign while three classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000713953	SCV001962319	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798505	SCV002043110	benign	Cardiomyopathy	2020-06-08	criteria provided, single submitter	clinical testing
GeneReviews	RCV000119019	SCV000153721	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2014-02-27	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000509179	SCV000607067	not provided	Tibial muscular dystrophy		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000713953	SCV001744916	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000154875	SCV001924228	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000713953	SCV001927038	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000713953	SCV001952059	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000713953	SCV001968772	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544417	SCV004760616	likely benign	TTN-related disorder	2020-09-22	no assertion criteria provided	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).