VCV000043386.23 - ClinVar

NM_000363.5(TNNI3):c.529AAG[1] (p.Lys178del)

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.

Conflicting classifications of pathogenicity
Pathogenic(4); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000363.5(TNNI3):c.529AAG[1] (p.Lys178del)

Variation ID: 43386 Accession: VCV000043386.23

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 19q13.42 19: 55154045-55154047 (GRCh38) [ NCBI UCSC ] 19: 55665413-55665415 (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	Jan 31, 2015	Feb 14, 2024	May 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000363.5:c.529AAG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000354.4:p.Lys178del	inframe deletion
NM_000363.5:c.532_534del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000363.4:c.532_534del
NC_000019.10:g.55154046TTC[1]
NC_000019.9:g.55665414TTC[1]
NG_007866.2:g.8683AAG[1]
NG_011829.2:g.189AAG[1]
LRG_432:g.8683AAG[1]
LRG_432t1:c.532_534del
LRG_679:g.189AAG[1]

... more HGVS ... less HGVS

Protein change

K178del

Other names

Canonical SPDI

NC_000019.10:55154044:CTTCTTC:CTTC

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.

Links

ClinGen: CA021828 dbSNP: rs397516351 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.
TNNI3		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	699	760

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.
Hypertrophic cardiomyopathy	Pathogenic (2)	criteria provided, single submitter	Nov 16, 2019	RCV000700121.14
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	May 4, 2023	RCV001781349.9
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Jan 30, 2023	RCV003114214.3

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.
Pathogenic (Jan 30, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003800738.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (4) PubMed: 12707239‚ 18403758‚ 27532257‚ 21533915 Comment: Variant summary: TNNI3 c.532_534delAAG (p.Lys178del, aka p.Lys177del) results in an in-frame deletion that is predicted to remove a Lysine amino acid residue from the encoded … (more) Variant summary: TNNI3 c.532_534delAAG (p.Lys178del, aka p.Lys177del) results in an in-frame deletion that is predicted to remove a Lysine amino acid residue from the encoded protein. The variant was absent in 248552 control chromosomes (gnomAD). The variant, c.532_534delAAG has been reported in the literature in individuals affected with hypertrophic and restrictive cardiomyopathy, including at least 2 de novo occurrences (e.g. Richard_2003, Morita_2008, van den Wijngaard_2011, Walsh_2017). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=2) / likely pathogenic (n=1), or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022365.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Uncertain significance (May 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501406.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (3) PubMed: 12707239‚ 21533915‚ 27532257 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (May 04, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002526371.4 First in ClinVar: Jun 18, 2022 Last updated: May 13, 2023	Comment: In-frame deletion of one amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency … (more) In-frame deletion of one amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21533915, 27532257, 18402758, 35456187, 12707239, 18403758) (less)
Pathogenic (Nov 16, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000828863.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 28492532‚ 12707239‚ 21533915‚ 27532257‚ 18402758 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available for this variant, and the functional significance … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant has been observed to be de novo in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239) and restrictive cardiomyopathy (PMID: 21533915). This variant has also been observed in several individuals with hypertrophic cardiomyopathy (PMID: 27532257, 18402758). ClinVar contains an entry for this variant (Variation ID: 43386). This variant is not present in population databases (ExAC no frequency). This variant, c.532_534delAAG, results in the deletion of 1 amino acid of the TNNI3 protein (p.Lys178del), but otherwise preserves the integrity of the reading frame. (less)
Pathogenic (Dec 02, 2009)	no assertion criteria provided Method: clinical testing	Hypertrophic cardiomyopathy Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059949.5 First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019	Publications: PubMed (2) PubMed: 18403758‚ 12707239 Number of individuals with the variant: 5

Comment:

Variant summary: TNNI3 c.532_534delAAG (p.Lys178del, aka p.Lys177del) results in an in-frame deletion that is predicted to remove a Lysine amino acid residue from the encoded protein. The variant was absent in 248552 control chromosomes (gnomAD). The variant, c.532_534delAAG has been reported in the literature in individuals affected with hypertrophic and restrictive cardiomyopathy, including at least 2 de novo occurrences (e.g. Richard_2003, Morita_2008, van den Wijngaard_2011, Walsh_2017). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=2) / likely pathogenic (n=1), or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

In-frame deletion of one amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21533915, 27532257, 18402758, 35456187, 12707239, 18403758)

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant has been observed to be de novo in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239) and restrictive cardiomyopathy (PMID: 21533915). This variant has also been observed in several individuals with hypertrophic cardiomyopathy (PMID: 27532257, 18402758). ClinVar contains an entry for this variant (Variation ID: 43386). This variant is not present in population databases (ExAC no frequency). This variant, c.532_534delAAG, results in the deletion of 1 amino acid of the TNNI3 protein (p.Lys178del), but otherwise preserves the integrity of the reading frame.

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
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy.	van den Wijngaard A	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2011	PMID: 21533915
Shared genetic causes of cardiac hypertrophy in children and adults.	Morita H	The New England journal of medicine	2008	PMID: 18403758
Miniature ponies: 2. Endocrinology of the oestrous cycle.	Ginther OJ	Reproduction, fertility, and development	2008	PMID: 18402758
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.	Richard P	Circulation	2003	PMID: 12707239

Text-mined citations for rs397516351 ...

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_000363.5(TNNI3):c.529AAG[1] (p.Lys178del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516351 ...