Submissions for variant NM_001267550.2(TTN):c.56686G>A (p.Val18896Met)

gnomAD frequency: 0.00004  dbSNP: rs370629962

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172305	SCV000054981	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000172305	SCV000237327	likely benign	not provided	2021-02-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362)
Invitae	RCV001087751	SCV000286730	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000242147	SCV000319985	uncertain significance	Cardiovascular phenotype	2018-09-12	criteria provided, single submitter	clinical testing	The p.V9831M variant (also known as c.29491G>A), located in coding exon 118 of the TTN gene, results from a G to A substitution at nucleotide position 29491. The valine at codon 9831 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). This amino acid position is well conserved in available 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 alteration remains unclear.
Eurofins Ntd Llc (ga)	RCV000172305	SCV000701090	uncertain significance	not provided	2016-10-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768983	SCV000900356	uncertain significance	Cardiomyopathy	2016-07-11	criteria provided, single submitter	clinical testing
Genetics and Genomics Program, Sidra Medicine	RCV001293199	SCV001434197	likely benign	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000172305	SCV003826574	uncertain significance	not provided	2022-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235091	SCV003934101	uncertain significance	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.48982G>A (p.Val16328Met) results in a conservative amino acid change located in the A band region of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 233146 control chromosomes (gnomAD). c.48982G>A has been reported in the literature in individuals affected with Sudden Arrhythmic Death Syndrome and cardiomyopathy, however authors classified the variant as VUS or likely benign (examples: Nunn_2016, Yeh_2019, Al-Shafai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34137518, 26498160, 31879508). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000172305	SCV004152367	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing