ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.104936G>C (p.Gly34979Ala)

gnomAD frequency: 0.00014  dbSNP: rs376634193
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000205837 SCV000261413 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2015-10-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000253506 SCV000318920 likely benign Cardiovascular phenotype 2020-05-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Eurofins Ntd Llc (ga) RCV000298099 SCV000334589 uncertain significance not provided 2015-09-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825259 SCV000966547 likely benign not specified 2019-01-02 criteria provided, single submitter clinical testing The p.Gly32411Ala variant in TTN is classified as likely benign because it has b een identified in 0.01% (18/128300) of European chromosomes by gnomAD (http://gn omad.broadinstitute.org) and was identified in trans with a likely pathogenic va riant. ACMG/AMP Criteria applied: BS1_Supporting, BP2.
GeneDx RCV000298099 SCV001785607 likely benign not provided 2019-02-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 31983221)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798686 SCV002042335 uncertain significance Cardiomyopathy 2020-05-12 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000298099 SCV003825589 uncertain significance not provided 2022-06-02 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004530234 SCV004118214 uncertain significance TTN-related disorder 2023-06-27 criteria provided, single submitter clinical testing The TTN c.104936G>C variant is predicted to result in the amino acid substitution p.Gly34979Ala. This variant was reported in a large cohort study of individuals with dilated cardiomyopathy (Reported as chr2:g.179396406 in Supp. Table 3 Mazzarotto et al 2020. PubMed ID: 31983221). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179396406-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000825259 SCV004121842 uncertain significance not specified 2023-10-02 criteria provided, single submitter clinical testing Variant summary: TTN c.97232G>C (p.Gly32411Ala) results in a non-conservative amino acid change in 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 8e-05 in 249104 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (8e-05 vs 0.00039), allowing no conclusion about variant significance. c.97232G>C has been reported in the literature in an individual from a Dilated Cardiomyopathy cohort (Mazzarotto_2020). 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. The following publication has been ascertained in the context of this evaluation (PMID: 31983221). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=4) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen RCV000298099 SCV004150176 uncertain significance not provided 2023-10-01 criteria provided, single submitter clinical testing

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