Submissions for variant NM_001267550.2(TTN):c.100447G>C (p.Glu33483Gln)

gnomAD frequency: 0.00019  dbSNP: rs368321767

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000713947	SCV000237884	likely benign	not provided	2021-05-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26272908)
Illumina Laboratory Services, Illumina	RCV000392156	SCV000420283	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	RCV000283303	SCV000420284	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	RCV000340707	SCV000420285	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	RCV000305798	SCV000420287	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	RCV000353303	SCV000420288	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	RCV000537271	SCV000642492	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617715	SCV000736499	uncertain significance	Cardiovascular phenotype	2018-09-19	criteria provided, single submitter	clinical testing	The p.E24418Q variant (also known as c.73252G>C), located in coding exon 184 of the TTN gene, results from a G to C substitution at nucleotide position 73252. The glutamic acid at codon 24418 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in a sudden unexplained death case with additional cardiac-related variants (as NM_001256850.1:c.95524G>C p.E31842Q in Santori M et al. Arch. Dis. Child., 2015 Oct;100:952-6). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Athena Diagnostics Inc	RCV000713947	SCV000844596	uncertain significance	not provided	2017-09-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000713947	SCV000855093	uncertain significance	not provided	2018-07-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764297	SCV000895316	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2018-10-31	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270047	SCV001448778	uncertain significance	Delayed speech and language development; Abnormality of eye movement; Generalized hypotonia; Abnormality of speech or vocalization; Delayed gross motor development; Hypotonia	2019-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282014	SCV002571881	uncertain significance	not specified	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.92743G>C (p.Glu30915Gln) results in a conservative amino acid change located in the A 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 0.00019 in 248440 control chromosomes, predominantly at a frequency of 0.00036 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00019 vs 0.00039), allowing no conclusion about variant significance. c.92743G>C has been reported in the literature as a VUS in settings of multigene panel testing and whole exome sequencing in individuals affected with various cardiomyopathies and in at least two cases of sudden cardiac death (e.g. Santori_2015, Nunn_2016, Forleo_2017, Minoche_2019). 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. Nine clinical submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Most classified the variant as VUS (n=7), and two classified the variant as benign (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000713947	SCV003819217	uncertain significance	not provided	2023-03-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000713947	SCV004150194	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TTN: PM2, BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486756	SCV004240211	likely benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000713947	SCV001741072	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000713947	SCV001926693	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000713947	SCV001952066	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000713947	SCV001972309	likely benign	not provided		no assertion criteria provided	clinical testing