VCV001806020.2 - ClinVar

NM_001276345.2(TNNT2):c.852-3C>A

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001276345.2(TNNT2):c.852-3C>A

Variation ID: 1806020 Accession: VCV001806020.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q32.1 1: 201359258 (GRCh38) [ NCBI UCSC ] 1: 201328386 (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	Dec 24, 2022	Apr 20, 2024	Sep 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001276345.2:c.852-3C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_000364.4:c.843-3C>A		intron variant
NM_001001430.3:c.822-3C>A		intron variant
NM_001001431.3:c.813-3C>A		intron variant
NM_001001432.3:c.804-3C>A		intron variant
NM_001276346.2:c.723-3C>A		intron variant
NM_001276347.2:c.822-3C>A		intron variant
NC_000001.11:g.201359258G>T
NC_000001.10:g.201328386G>T
NG_007556.1:g.23420C>A
LRG_431:g.23420C>A
LRG_431t1:c.852-3C>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:201359257:G:T

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

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.
TNNT2		No evidence available	No evidence available	GRCh38 GRCh37	959	978

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 2	Uncertain significance (1)	criteria provided, single submitter	May 26, 2020	RCV002470304.1
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Sep 17, 2023	RCV004007473.2

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.
Uncertain significance (May 26, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767050.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 18612386‚ 23396983‚ 25849606 Comment: Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3A-VUS. Following criteria are met: 0104 - Dominant Negative is a mechanism of … (more) Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3A-VUS. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene (PMID:18612386). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0209 - Non-canonical splice variant located in inton 15 of 15, proven to affect splicing/expression of the transcript with uncertain effect on protein structure (PMID:25849606). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide has low conservation. (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in patients with hypertrophic cardiomyopathy (PMID:23396983; PMID:25849606) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
Uncertain Significance (Sep 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004829184.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (3) PubMed: 23396983‚ 25351510‚ 25849606 Comment: This variant causes a C to A nucleotide substitution at the -3 position of intron 15 of the TNNT2 gene. Splice site prediction tools suggest … (more) This variant causes a C to A nucleotide substitution at the -3 position of intron 15 of the TNNT2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional mini-gene assay has shown that this variant may cause abnormal splicing (PMID: 25849606). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 23396983, 25351510) and in an individual affected with cardiomyopathy (PMID: 25849606). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 1 Zygosity: Single Heterozygote

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3A-VUS. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene (PMID:18612386). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0209 - Non-canonical splice variant located in inton 15 of 15, proven to affect splicing/expression of the transcript with uncertain effect on protein structure (PMID:25849606). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide has low conservation. (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in patients with hypertrophic cardiomyopathy (PMID:23396983; PMID:25849606) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Comment:

This variant causes a C to A nucleotide substitution at the -3 position of intron 15 of the TNNT2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional mini-gene assay has shown that this variant may cause abnormal splicing (PMID: 25849606). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 23396983, 25351510) and in an individual affected with cardiomyopathy (PMID: 25849606). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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
Functional characterization of putative novel splicing mutations in the cardiomyopathy-causing genes.	Millat G	DNA and cell biology	2015	PMID: 25849606
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.	Lopes LR	Journal of medical genetics	2013	PMID: 23396983
The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy.	Ahmad F	PloS one	2008	PMID: 18612386

Text-mined citations for this variant ...

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001276345.2(TNNT2):c.852-3C>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...