ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.90991C>T (p.Pro30331Ser) (rs75022916)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184964 SCV000237739 likely benign not specified 2017-11-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000618251 SCV000735460 likely benign Cardiovascular phenotype 2020-09-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000697121 SCV000825715 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-06-20 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 30331 of the TTN protein (p.Pro30331Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs75022916, ExAC 0.07%). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 202973). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. This variant identified in the TTN gene is located in the A band of the resulting protein (PMID: 25589632). It is unclear how this variant impacts the function of this protein. 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000728236 SCV000855782 uncertain significance not provided 2017-07-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000184964 SCV001360678 uncertain significance not specified 2019-11-25 criteria provided, single submitter clinical testing Variant summary: TTN c.83287C>T (p.Pro27763Ser) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 248746 control chromosomes, predominantly at a frequency of 0.00065 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (4.4e-05 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.83287C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions (evaluation after 2014) cite the variant three times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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