ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.61992C>G (p.Asn20664Lys)

gnomAD frequency: 0.00005  dbSNP: rs376455983
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000155829 SCV000205540 uncertain significance not specified 2013-11-14 criteria provided, single submitter clinical testing The Asn18096Lys variant in TTN has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 2/8212 European American chromoso mes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu; dbSNP r s376455983). Computational analyses (amino acid biochemical properties, conserv ation, PolyPhen-2, AlignGVGD, SIFT) do not provide strong evidence for or agains t an impact to the protein. Additional information is needed to fully assess the clinical significance of the Asn18096Lys variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000687436 SCV000815001 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-05-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 20664 of the TTN protein (p.Asn20664Lys). There is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs376455983, ExAC 0.004%). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 179045). This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV002225457 SCV002504521 likely benign not provided 2019-06-26 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Ambry Genetics RCV002453520 SCV002613113 uncertain significance Cardiovascular phenotype 2020-09-11 criteria provided, single submitter clinical testing The p.N11599K variant (also known as c.34797C>G), located in coding exon 131 of the TTN gene, results from a C to G substitution at nucleotide position 34797. The asparagine at codon 11599 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly 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.

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