VCV000626247.8 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 626247 Accession: VCV000626247.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.1 1: 74492217 (GRCh38) [ NCBI UCSC ] 1: 74957901 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 29, 2019	Feb 20, 2024	Dec 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001382280.1:c.-26-8842C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_015978.3:c.2302G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057062.1:p.Glu768Lys	missense
NM_001112808.3:c.2605G>A	NP_001106279.3:p.Glu869Lys	missense
NM_001364666.2:c.-8-11249C>T		intron variant
NC_000001.11:g.74492217G>A
NC_000001.10:g.74957901G>A
NG_032939.2:g.298965G>A
LRG_678:g.298965G>A
LRG_678t1:c.2302G>A	LRG_678p1:p.Glu768Lys

... more HGVS ... less HGVS

Protein change

E768K, E869K

Other names

Canonical SPDI

NC_000001.11:74492216:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

OMIM: 613932.0004 dbSNP: rs202238194 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FPGT-TNNI3K	-	-	-	GRCh38 GRCh37	-	1116
LRRC53	-	-	-	GRCh38	-	110
TNNI3K		-	-	GRCh38 GRCh37	-	1055

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Atrial conduction disease	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV000768402.6
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 28, 2023	RCV001869062.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Atrial conduction disease Affected status: yes Allele origin: inherited	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000965764.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Atrial conduction disease (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002766866.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 30010057‚ 34203974 Comment: 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 … (more) 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 (less)
Likely pathogenic (Apr 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Atrial conduction disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002794624.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Atrial conduction disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004049443.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023
Pathogenic (Dec 28, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002232695.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 30010057 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 23, 2019)	no assertion criteria provided Method: literature only	CARDIAC CONDUCTION DISEASE WITH OR WITHOUT DILATED CARDIOMYOPATHY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000899161.1 First in ClinVar: Apr 29, 2019 Last updated: Apr 29, 2019	Publications: PubMed (1) PubMed: 30010057 Comment on evidence: In all 23 affected individuals from 3 unrelated large multigenerational families with cardiac conduction disease with or without dilated cardiomyopathy (CCDD; 616117), Podliesna et al. … (more) In all 23 affected individuals from 3 unrelated large multigenerational families with cardiac conduction disease with or without dilated cardiomyopathy (CCDD; 616117), Podliesna et al. (2019) identified heterozygosity for a c.2302G-A transition (c.2302G-A, NM_015978.2) in exon 23 of the TNNI3K gene, resulting in a glu768-to-lys (E768K) substitution at a highly conserved residue within the C terminus. No clinical information was available for 3 additional family members who tested positive for the E768K variant, or for 1 obligate carrier. The mutation was very rare in the general population, with a minor allele frequency of 0.0016% in the gnomAD database. Autophosphorylation assay in transfected HEK293A cells demonstrated significantly increased kinase activity with the mutant compared to wildtype TNNI3K. (less)

Comment:

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

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment.	Pham C	International journal of molecular sciences	2021	PMID: 34203974
Supraventricular tachycardias, conduction disease, and cardiomyopathy in 3 families with the same rare variant in TNNI3K (p.Glu768Lys).	Podliesna S	Heart rhythm	2019	PMID: 30010057

Text-mined citations for rs202238194 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs202238194 ...