ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter)
Variation ID: 177636 Accession: VCV000177636.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201359217 (GRCh38) [ NCBI UCSC ] 1: 201328345 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 11, 2015 Feb 28, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.890G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Trp297Ter nonsense NM_000364.4:c.881G>A NP_000355.2:p.Trp294Ter nonsense NM_001001430.3:c.860G>A NP_001001430.1:p.Trp287Ter nonsense NM_001001431.3:c.851G>A NP_001001431.1:p.Trp284Ter nonsense NM_001001432.3:c.842G>A NP_001001432.1:p.Trp281Ter nonsense NM_001276346.2:c.761G>A NP_001263275.1:p.Trp254Ter nonsense NM_001276347.2:c.860G>A NP_001263276.1:p.Trp287Ter nonsense NC_000001.11:g.201359217C>T NC_000001.10:g.201328345C>T NG_007556.1:g.23461G>A LRG_431:g.23461G>A LRG_431t1:c.890G>A LRG_431p1:p.Trp297Ter - Protein change
- W287*, W294*, W281*, W284*, W254*, W297*
- Other names
- p.W287*:TGG>TAG
- Canonical SPDI
- NC_000001.11:201359216:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 | ||
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HI score
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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. |
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TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
898 | - |
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. |
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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000154218.10 | |
Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2022 | RCV000159326.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2016 | RCV000211869.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000627785.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 6, 2018 | RCV000824774.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 6, 2023 | RCV001170984.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 13, 2023 | RCV002444634.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003453151.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003453152.1 |
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. |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe)
Accession: SCV000256206.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 2
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Pathogenic
(Apr 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000577979.1
First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016 |
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Pathogenic
(Apr 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203872.5
First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019 |
Comment:
The p.Trp287X variant in TNNT2 has been identified in >20 individuals with HCM a nd segregated with disease in 7 affected relatives from 6 families … (more)
The p.Trp287X variant in TNNT2 has been identified in >20 individuals with HCM a nd segregated with disease in 7 affected relatives from 6 families (Richard 2003 , Gandjbakhch 2010, Brito 2012, D. Brito pers comm, GeneDx pers comm; LMM data). Adult patients who carried this variant were noted to have mild to moderate HCM and ECG abnormalities (D. Brito pers comm). In addition, the p.Trp278X variant has been identified in 1/32874 Latino chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org/ dbSNP rs727504247). This nonsens e variant leads to a premature termination codon at position 287. This alteratio n occurs within the last exon and may therefore escape nonsense mediated decay ( NMD), resulting in a truncated protein that is lacking the last 2 amino acids. I n summary, this variant meets our criteria to be classified as pathogenic for HC M in an autosomal dominant manner based upon case observations and segregation s tudies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PM4_Supporting. (less)
Number of individuals with the variant: 17
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Likely pathogenic
(Mar 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000209272.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported to segregate with disease in two families, but no details were provided (Brito et al., 2012); Not observed at significant frequency in large population … (more)
Reported to segregate with disease in two families, but no details were provided (Brito et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last two amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Limited functional studies using human induced pluripotent stem cell-derived cardiomyocytes suggest that this variant impacts protein function (Pettinato et al., 2020); however additional studies are needed to validate the functional effect of this variant in vivo; This variant is associated with the following publications: (PMID: 12707239, 27532257, 20439259, 23396983, 25351510, 26936621, 22857948, 20031601, 30297972, 33025817, 30975432) (less)
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Pathogenic
(Jun 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333647.3
First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Oct 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502766.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Aug 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 2
Dilated cardiomyopathy 1D Cardiomyopathy, familial restrictive, 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002800613.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Sep 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002677845.2
First in ClinVar: Nov 29, 2022 Last updated: Oct 28, 2023 |
Comment:
The p.W287* variant (also known as c.860G>A), located in coding exon 15 of the TNNT2 gene, results from a G to A substitution at nucleotide … (more)
The p.W287* variant (also known as c.860G>A), located in coding exon 15 of the TNNT2 gene, results from a G to A substitution at nucleotide position 860. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration has been detected in multiple hypertrophic cardiomyopathy (HCM) cohorts and has been reported to segregate with disease, but segregation details were limited (Richard P et al. Circulation, 2003 May;107:2227-32; Brito D et al. Rev Port Cardiol, 2012 Sep;31:577-87; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Bales ND et al. Pediatr Cardiol, 2016 Jun;37:845-51; Walsh R et al. Genet. Med., 2017 02;19:192-203). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Although premature stop codons are typically deleterious in nature, loss of function of TNNT2 has not been clearly established as a mechanism of disease. This stop codon, however, occurs at the 3' terminus of TNNT2, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 2 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004180471.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 3
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004180470.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1D
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004180469.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 3
Hypertrophic cardiomyopathy 2 Dilated cardiomyopathy 1D
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000253859.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp287*) in the TNNT2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Trp287*) in the TNNT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the TNNT2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 20439259, 22857948, 23396983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177636). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 16, 2012)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280537.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Trp287Stop (c.860 G>A, W287X) in TNNT2. Given strong case data, absence in controls, and segregation in multiple families, (all reviewed below) we consider this variant likely disease causing. The variant has been seen in at least 14 unrelated cases of HCM (not including the patient's family). There is weak segregation data in at least 6 families. Brito et al (2012) observed the variant in 3 of 77 unrelated individuals with HCM in their Portuguese cohort. Two of these patients have affected relatives and the authors note the variant segregated with disease however they do not provide details on the number of affected relatives with the variant. Richard et al (2003) observed the variant in 2 unrelated patients in their cohort of 197 HCM patients from France (likely redundant with Gandjbackhch et al 2010 from the same group). Bill McKenna's group observed the variant in 1 out of 223 HCM patients from their UK cohort (Lopes et al 2013). GeneDx shared they've seen it in one patient tested for HCM (presumably this family) and two tested with a DCM panel. I have requested phenotype and ancestry data. A genetic testing lab shared with us that they have seen the variant in multiple patients with HCM with segregation in some families. Of note, most of these cases were Portuguese. The variant affects one of the last residues in the protein, though it is a bit unclear how far to the end (the labs and papers conflict). The testing lab reports we have do not provide the transcript they used. Per another source, this affects the second last residue of the protein, creating a stop codon where there would normally be a tryptohan. It would lead to loss of the last two amino acids. Unlike nonsense variants that occur earlier in the amino acid sequence this variant would most likely not lead to nonsense-mediate mRNA decay. Notably, the end of the protein is highly conserved across mammals In total the variant has not been seen in ~6400 published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6300 Caucasian and African American individuals (as of February 18th, 2014). It is also not listed in dbSNP. The variant was not observed in 100 healthy adults analyzed by Richard et al (2003). Unfortunately there are not any Portuguese controls available. (less)
Number of individuals with the variant: 15
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928111.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951833.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpText-mined citations for rs727504247 ...
HelpRecord last updated Mar 05, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.