ClinVar Genomic variation as it relates to human health
NM_001377142.1(PLCB4):c.1898G>A (p.Arg633His)
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_001377142.1(PLCB4):c.1898G>A (p.Arg633His)
Variation ID: 31639 Accession: VCV000031639.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p12.2 20: 9409080 (GRCh38) [ NCBI UCSC ] 20: 9389727 (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 Mar 6, 2015 Sep 9, 2023 Aug 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001377142.1:c.1898G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001364071.1:p.Arg633His missense NM_000933.4:c.1862G>A NP_000924.3:p.Arg621His missense NM_001172646.2:c.1898G>A NP_001166117.1:p.Arg633His missense NM_001377134.2:c.1862G>A NP_001364063.1:p.Arg621His missense NM_001377135.1:c.1862G>A NP_001364064.1:p.Arg621His missense NM_001377136.1:c.1862G>A NP_001364065.1:p.Arg621His missense NM_001377143.1:c.1898G>A NP_001364072.1:p.Arg633His missense NM_182797.3:c.1862G>A NP_877949.2:p.Arg621His missense NC_000020.11:g.9409080G>A NC_000020.10:g.9389727G>A NG_032790.2:g.345027G>A Q15147:p.Arg621His - Protein change
- R621H, R633H
- Other names
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- Canonical SPDI
- NC_000020.11:9409079:G:A
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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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0.00000 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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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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PLCB4 | - | - |
GRCh38 GRCh37 |
250 | 292 |
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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 28, 2023 | RCV000024335.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 17, 2012 | RCV000191053.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2017 | RCV000623188.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2019 | RCV001249753.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 30, 2022 | RCV002281044.3 |
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. |
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Pathogenic
(Sep 17, 2012)
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criteria provided, single submitter
Method: research
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Auriculocondylar syndrome 1
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000246133.1
First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
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Pathogenic
(Sep 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742771.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian
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Pathogenic
(Dec 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Auriculocondylar syndrome
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001423786.2
First in ClinVar: Jul 25, 2020 Last updated: Mar 04, 2023 |
Comment:
The PLCB4 c.1862G>A (p.Arg621His) variant is a missense variant. Across a selection of the available literature, the p.Arg621His variant has been identified in a heterozygous … (more)
The PLCB4 c.1862G>A (p.Arg621His) variant is a missense variant. Across a selection of the available literature, the p.Arg621His variant has been identified in a heterozygous state in at least seven individuals of a multi-generational family segregating with auriculocondylar syndrome (ACS), and in one sporadic case of ACS, in which the variant occurred in a de novo state (Rieder et al. 2012; Gordon et al. 2013). The p.Arg621His variant was not found in 10758 control alleles and is not reported in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare (Rieder et al. 2012). The p.Arg621His variant is highly conserved through evolution and is located in a catalytic domain of the PCLB4 protein in a region described as a hotspot for missense variation associated with ACS (Gordon et al. 2013). Additionally, at least two more missense variants with different amino acid alterations at the Arg61 residue have been reported in the literature in affected individuals (Gordon et al. 2013). Based on the collective evidence and application of the ACMG criteria, the p.Arg621His variant is classified as pathogenic for auriculocondylar syndrome. (less)
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Pathogenic
(Aug 30, 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: SCV002569805.2
First in ClinVar: Sep 10, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23315542, 33131036, 32201334, 35170830, 22560091) (less)
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Pathogenic
(Jan 05, 2023)
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criteria provided, single submitter
Method: research
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Auriculocondylar syndrome 2
Affected status: yes
Allele origin:
maternal
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Tammimies Lab, Karolinska Institutet
Accession: SCV004024451.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
Sex: female
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Pathogenic
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Auriculocondylar syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004032262.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
Criteria applied: PM5_STR,PS2_MOD,PS4_MOD,PM1,PM2_SUP,PP3,PP4
Clinical Features:
Full cheeks (present) , Mandibular condyle hypoplasia (present) , Micrognathia (present) , Question mark ear (present)
Sex: female
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Pathogenic
(Mar 01, 2013)
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no assertion criteria provided
Method: literature only
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AURICULOCONDYLAR SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045626.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 06, 2015 |
Comment on evidence:
In affected members of a large 4-generation pedigree with auriculocondylar syndrome (ARCND2; 614669), originally reported by Storm et al. (2005) (family 1), Rieder et al. … (more)
In affected members of a large 4-generation pedigree with auriculocondylar syndrome (ARCND2; 614669), originally reported by Storm et al. (2005) (family 1), Rieder et al. (2012) identified heterozygosity for a 1862G-A transition in the PLCB4 gene, resulting in an arg621-to-his (R621H) substitution at a highly conserved residue in the catalytic site. The mutation segregated with disease in the family and was not found in 10,758 control chromosomes. In a boy from Oman with ARCND, Gordon et al. (2013) identified heterozygosity for a de novo R621H mutation in the PLCB4 gene. His unaffected parents and brother did not carry the mutation. (less)
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Pathogenic
(Dec 30, 2017)
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no assertion criteria provided
Method: curation
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Auriculocondylar syndrome 2
Affected status: yes
Allele origin:
unknown
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Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891540.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Geographic origin: Middle East
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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
HelpTitle | Author | Journal | Year | Link |
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Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome. | Gordon CT | Journal of medical genetics | 2013 | PMID: 23315542 |
A human homeotic transformation resulting from mutations in PLCB4 and GNAI3 causes auriculocondylar syndrome. | Rieder MJ | American journal of human genetics | 2012 | PMID: 22560091 |
Auriculo-condylar syndrome is associated with highly variable ear and mandibular defects in multiple kindreds. | Storm AL | American journal of medical genetics. Part A | 2005 | PMID: 16114046 |
Text-mined citations for rs397514481 ...
HelpRecord last updated Sep 16, 2023
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.