ClinVar Miner

Submissions for variant NM_015978.3(TNNI3K):c.2302G>A (p.Glu768Lys)

gnomAD frequency: 0.00002  dbSNP: rs202238194
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000768402 SCV000965764 likely pathogenic Atrial conduction disease 2016-01-01 criteria provided, single submitter clinical testing
Invitae RCV001869062 SCV002232695 pathogenic not provided 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 768 of the TNNI3K protein (p.Glu768Lys). This variant is present in population databases (rs202238194, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of TNNI3K-related conditions (PMID: 30010057). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 626247). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TNNI3K function (PMID: 30010057). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000768402 SCV002766866 pathogenic Atrial conduction disease 2022-03-31 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with cardiac conduction disease with or without dilated cardiomyopathy (MIM#616117). Loss of function and dominant negative have also been suggested as mechanisms, but current evidence is limited (PMIDs: 30010057, 34203974). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated serine rich C-terminus domain (PMID: 30010057). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been observed in 24 affected individuals from four families with cardiac phenotypes, predominantly supraventricular tachycardias that in some individuals occurred together with cardiac conduction disease and/or DCM (ClinVar, PMID: 30010057). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been observed to segregate with disease in many affected individuals across three generations of three large families (PMID: 30010057). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Western blot studies in transfected HEK293A cells have shown this variant displays significantly increased autophosphorylation compared to wild type cells (PMID: 30010057). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV000768402 SCV002794624 likely pathogenic Atrial conduction disease 2022-04-20 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000768402 SCV004049443 likely pathogenic Atrial conduction disease 2023-04-11 criteria provided, single submitter clinical testing
OMIM RCV000768402 SCV000899161 pathogenic Atrial conduction disease 2019-04-23 no assertion criteria provided literature only

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