Submissions for variant NM_001267550.2(TTN):c.100432T>G (p.Trp33478Gly)

gnomAD frequency: 0.00018  dbSNP: rs372304158

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000713946	SCV000237883	likely benign	not provided	2021-05-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24459294, 26272908)
Illumina Laboratory Services, Illumina	RCV000390641	SCV000420289	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	RCV000299494	SCV000420290	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	RCV000356693	SCV000420291	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	RCV000331220	SCV000420293	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	RCV000369666	SCV000420294	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524719	SCV000642491	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621440	SCV000736498	uncertain significance	Cardiovascular phenotype	2018-09-19	criteria provided, single submitter	clinical testing	The p.W24413G variant (also known as c.73237T>G), located in coding exon 184 of the TTN gene, results from a T to G substitution at nucleotide position 73237. The tryptophan at codon 24413 is replaced by glycine, an amino acid with highly dissimilar properties. This variant was reported in a sudden unexplained death case (as NM_001256850.1:c.95509T>G p.W31837G in Santori M et al. Arch. Dis. Child., 2015 Oct;100:952-6) and in an individual from a congenital heart defect cohort (as NM_001267550.1: c.100432T>G p.W33478G in Grunert M et al. Hum. Mol. Genet., 2014 Jun;23:3115-28); however, both of these individuals also had additional cardiac-related variants. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Athena Diagnostics	RCV000713946	SCV000844595	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000713946	SCV000855092	uncertain significance	not provided	2018-07-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764298	SCV000895317	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	RCV001270048	SCV001448779	uncertain significance	Delayed speech and language development; Abnormality of eye movement; Generalized hypotonia; Abnormal speech pattern; Delayed gross motor development; Hypotonia	2019-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282013	SCV002571882	uncertain significance	not specified	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.92728T>G (p.Trp30910Gly) results in a non-conservative amino acid change located in the A-band 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 0.00019 in 248518 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.92728T>G 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.Grunert_2014, 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	RCV000713946	SCV003827347	uncertain significance	not provided	2023-03-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000713946	SCV004150195	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TTN: PM2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486755	SCV004240210	likely benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing