Submissions for variant NM_001267550.2(TTN):c.56947G>A (p.Ala18983Thr)

gnomAD frequency: 0.00007  dbSNP: rs377000174

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213289	SCV000272694	likely benign	not specified	2018-11-09	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000726732	SCV000617124	likely benign	not provided	2020-12-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22526018, 23446887, 31983221)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548016	SCV000643404	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-06-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726732	SCV000702564	uncertain significance	not provided	2016-10-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768979	SCV000900352	uncertain significance	Cardiomyopathy	2021-11-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213289	SCV001821373	uncertain significance	not specified	2021-08-23	criteria provided, single submitter	clinical testing	Variant summary: TTN c.49243G>A (p.Ala16415Thr) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 249438 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (9.6e-05 vs 0.00039), allowing no conclusion about variant significance. c.49243G>A has been reported in the literature in individuals affected with Dilated cardiomyopathy, Hypertrophic cardiomyopathy and Muscular dystrophy as well as in one healthy control (Vasli_2012, Lopes_2013, Mazzarotto_2020). These reports 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. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002433937	SCV002746203	uncertain significance	Cardiovascular phenotype	2018-07-05	criteria provided, single submitter	clinical testing	The p.A9918T variant (also known as c.29752G>A), located in coding exon 118 of the TTN gene, results from a G to A substitution at nucleotide position 29752. The alanine at codon 9918 is replaced by threonine, an amino acid with similar properties. This variant (reported as p.A16415T) was detected in the compound heterozygous state with TTN p.V998M (reported as p.V1034M) in a patient with limb girdle muscular dystrophy and her affected brother (Vasli N et al. Acta Neuropathol. 2012;124:273-83). This alteration was also identified in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. J. Med. Genet. 2013;50:228-39). This amino acid position is highly conserved through mammals but not in all 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 alteration remains unclear.
Revvity Omics, Revvity	RCV000726732	SCV003821023	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000726732	SCV005413074	uncertain significance	not provided	2023-12-19	criteria provided, single submitter	clinical testing	BP4
Athena Diagnostics	RCV000726732	SCV005622154	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is not damaging.
Clinical Genetics, Academic Medical Center	RCV000726732	SCV001925277	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000726732	SCV001963541	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734868	SCV005353164	uncertain significance	TTN-related disorder	2024-06-25	no assertion criteria provided	clinical testing	The TTN c.56947G>A variant is predicted to result in the amino acid substitution p.Ala18983Thr. This variant was reported in the compound heterozygous state with another TTN missense variant in a patient with muscular dystrophy (Reported as p.Ala16415Thr, Table 2, Patient O. Vasli et al 2012. PubMed ID: 22526018). This variant was also reported in one individual from a large dilated cardiomyopathy cohort study (Supp. Table 3, Mazzarotto F et al 2020. PubMed ID: 31983221). This variant is reported in 0.018% of alleles in individuals of European (non-Finnish) descent in gnomAD, which is likely too common for autosomal dominant TTN-related disorders. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.