ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.99901G>A (p.Glu33301Lys) (rs72648278)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000242155 SCV000320031 uncertain significance Cardiovascular phenotype 2015-08-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725311 SCV000335952 uncertain significance not provided 2015-10-13 criteria provided, single submitter clinical testing
GeneDx RCV000040890 SCV000237874 uncertain significance not specified 2017-04-05 criteria provided, single submitter clinical testing A second published variant of uncertain significance has been identified in the TTN gene. The E31660K variant, also denoted as E24236K and E33301K due to the use of an alternate transcripts, has been previously reported in one individual with DCM and three individuals with HCM (Lopes et al., 2013; Franaszcyk et al., 2017). Of these individuals with HCM, one harbored additional cardiogenetic variants, including the L5425F variant in the TTN gene (Lopes et al., 2013). Additionally, this variant is observed in 32/65524 (0.049%) alleles from individuals of Non-Finnish European ancestry, and in 3/6548 (0.046%) alleles from individuals of Finnish European ancestry, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The E31660K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position where only amino acids with similar properties to glutamic acid (E) are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, although this missense variant is located in the A-band region of titin, the majority of pathogenic variants in the TTN gene associated with DCM are truncating variants in this region of titin (Herman et al., 2012).
Illumina Clinical Services Laboratory,Illumina RCV000390934 SCV000420349 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000297253 SCV000420350 uncertain significance Myopathy, early-onset, with fatal cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000354426 SCV000420351 uncertain significance Distal myopathy Markesbery-Griggs type 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000390707 SCV000420352 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000301140 SCV000420353 uncertain significance Hereditary myopathy with early respiratory failure 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000367561 SCV000420354 uncertain significance Limb-Girdle Muscular Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000206544 SCV000261431 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040890 SCV000064581 uncertain significance not specified 2015-08-12 criteria provided, single submitter clinical testing The p.Glu30733Lys variant in TTN has been identified by our laboratory in 2 indi viduals with HCM, one of whom also carried a possible disease-causing variant in another gene. This variant has been identified in 32/65524 European American ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs72648278). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summa ry, the clinical significance of the p.Glu30733Lys variant is uncertain.

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