Reported in a patient who had an alternate explanation for disease (Guillen Sacoto et al., 2020) and in two siblings with a neurodevelopmental disorder who inherited the variant from an unaffected parent (Wang et al., 2020); In silico analysis supports that this missense variant has 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: 33547006, 32693025, 33004838)
ClinVar Genomic variation as it relates to human health
NM_207037.2(TCF12):c.1808G>A (p.Arg603Gln)
Germline
Classification
Help
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.
(3)
Help
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
Likely pathogenic(1); Uncertain significance(2)
Likely pathogenic(1); Uncertain significance(2)
3
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_207037.2(TCF12):c.1808G>A (p.Arg603Gln)
Variation ID: 987901 Accession: VCV000987901.4
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q21.3 15: 57273092 (GRCh38) [ NCBI UCSC ] 15: 57565290 (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 7, 2020 Nov 24, 2024 Dec 21, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_207037.2:c.1808G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996920.1:p.Arg603Gln missense NM_001306219.3:c.1298G>A NP_001293148.1:p.Arg433Gln missense NM_001306220.3:c.1028G>A NP_001293149.1:p.Arg343Gln missense NM_001322151.2:c.1808G>A NP_001309080.1:p.Arg603Gln missense NM_001322152.2:c.1805G>A NP_001309081.1:p.Arg602Gln missense NM_001322154.2:c.1151G>A NP_001309083.1:p.Arg384Gln missense NM_001322156.2:c.1634G>A NP_001309085.1:p.Arg545Gln missense NM_001322157.3:c.1736G>A NP_001309086.1:p.Arg579Gln missense NM_001322158.2:c.1562G>A NP_001309087.1:p.Arg521Gln missense NM_001322159.3:c.1808G>A NP_001309088.1:p.Arg603Gln missense NM_001322161.2:c.1805G>A NP_001309090.1:p.Arg602Gln missense NM_001322162.2:c.1808G>A NP_001309091.1:p.Arg603Gln missense NM_001322164.2:c.1772G>A NP_001309093.1:p.Arg591Gln missense NM_001322165.2:c.1736G>A NP_001309094.1:p.Arg579Gln missense NM_003205.4:c.1736G>A NP_003196.1:p.Arg579Gln missense NM_207036.1:c.1808G>A NM_207036.2:c.1808G>A NP_996919.1:p.Arg603Gln missense NM_207037.1:c.1808G>A NM_207038.2:c.1736G>A NP_996921.1:p.Arg579Gln missense NM_207040.2:c.1226G>A NP_996923.1:p.Arg409Gln missense NC_000015.10:g.57273092G>A NC_000015.9:g.57565290G>A NG_033851.2:g.360003G>A - Protein change
- R343Q, R384Q, R409Q, R433Q, R521Q, R545Q, R579Q, R591Q, R602Q, R603Q
- Other names
- -
- Canonical SPDI
- NC_000015.10:57273091:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| TCF12 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
383 | 405 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 5, 2022 | RCV002225821.2 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Dec 21, 2023 | RCV001269305.3 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Nov 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
TCF12-related craniosynostosis
Affected status: unknown
Allele origin:
de novo
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV001448652.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002504290.2
First in ClinVar: Apr 29, 2022 Last updated: Mar 04, 2023 |
Comment:
Reported in a patient who had an alternate explanation for disease (Guillen Sacoto et al., 2020) and in two siblings with a neurodevelopmental disorder who … (more)
Reported in a patient who had an alternate explanation for disease (Guillen Sacoto et al., 2020) and in two siblings with a neurodevelopmental disorder who inherited the variant from an unaffected parent (Wang et al., 2020); In silico analysis supports that this missense variant has 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: 33547006, 32693025, 33004838) (less)
|
|
|
Uncertain significance
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
TCF12-related craniosynostosis
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005400288.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypogonadotropic hypogonadism 26 with or without anosmia (MIM#619718), and craniosynostosis 3 (MIM#615314). There is no genotype phenotype correlation, where the same variant can cause both phenotypes or a blend (PMID:32620954). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, where an unaffected heterozygous parent had affected heterozygous children (PMID: 32620954). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated HLH domain (DECIPHER). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. An alternative change (p.(R603W)), was reported in ClinVar once as VUS, and once as de novo and likely pathogenic (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and as a VUS (ClinVar, PMID:33004838). This variant was also reported as de novo and a VUS in an individual with growth delay, hearing loss and absent seizures who had another alternate diagnosis, and as de novo and likely pathogenic in an individual with congenital diaphragmatic hernia, hypotonia and asymmetric ventriculomegaly (PMID:33004838, 32693025, 33461977). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypogonadotropic hypogonadism 26 with or without anosmia (MIM#619718), and craniosynostosis 3 (MIM#615314). There is no genotype phenotype correlation, where the same variant can cause both phenotypes or a blend (PMID:32620954). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, where an unaffected heterozygous parent had affected heterozygous children (PMID: 32620954). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated HLH domain (DECIPHER). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. An alternative change (p.(R603W)), was reported in ClinVar once as VUS, and once as de novo and likely pathogenic (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and as a VUS (ClinVar, PMID:33004838). This variant was also reported as de novo and a VUS in an individual with growth delay, hearing loss and absent seizures who had another alternate diagnosis, and as de novo and likely pathogenic in an individual with congenital diaphragmatic hernia, hypotonia and asymmetric ventriculomegaly (PMID:33004838, 32693025, 33461977). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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:
Reported in a patient who had an alternate explanation for disease (Guillen Sacoto et al., 2020) and in two siblings with a neurodevelopmental disorder who inherited the variant from an unaffected parent (Wang et al., 2020); In silico analysis supports that this missense variant has 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: 33547006, 32693025, 33004838)
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypogonadotropic hypogonadism 26 with or without anosmia (MIM#619718), and craniosynostosis 3 (MIM#615314). There is no genotype phenotype correlation, where the same variant can cause both phenotypes or a blend (PMID:32620954). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, where an unaffected heterozygous parent had affected heterozygous children (PMID: 32620954). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated HLH domain (DECIPHER). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. An alternative change (p.(R603W)), was reported in ClinVar once as VUS, and once as de novo and likely pathogenic (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and as a VUS (ClinVar, PMID:33004838). This variant was also reported as de novo and a VUS in an individual with growth delay, hearing loss and absent seizures who had another alternate diagnosis, and as de novo and likely pathogenic in an individual with congenital diaphragmatic hernia, hypotonia and asymmetric ventriculomegaly (PMID:33004838, 32693025, 33461977). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH. | Scott TM | Journal of medical genetics | 2022 | PMID: 33461977 |
| Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. | Wang T | Nature communications | 2020 | PMID: 33004838 |
| De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism. | Guillen Sacoto MJ | American journal of human genetics | 2020 | PMID: 32693025 |
| A 'one-tube' synthesis of a selective fluorescence 'turn off/on' DNA probe based on a C-phycocyanin-graphene oxide (CPC-GO) bio composite. | Ghosh T | International journal of biological macromolecules | 2020 | PMID: 32629054 |
| TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci. | Davis EE | Human molecular genetics | 2020 | PMID: 32620954 |
Text-mined citations for rs1349009265 ...
HelpThese 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 Nov 25, 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.