ClinVar Genomic variation as it relates to human health
NM_001384140.1(PCDH15):c.841A>G (p.Thr281Ala)
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_001384140.1(PCDH15):c.841A>G (p.Thr281Ala)
Variation ID: 1343722 Accession: VCV001343722.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 54317306 (GRCh38) [ NCBI UCSC ] 10: 56077066 (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 12, 2022 Oct 4, 2023 Aug 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384140.1:c.841A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371069.1:p.Thr281Ala missense NM_033056.4:c.841A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149045.3:p.Thr281Ala missense NM_001142763.2:c.856A>G NP_001136235.1:p.Thr286Ala missense NM_001142764.2:c.841A>G NP_001136236.1:p.Thr281Ala missense NM_001142765.2:c.841A>G NP_001136237.1:p.Thr281Ala missense NM_001142766.2:c.841A>G NP_001136238.1:p.Thr281Ala missense NM_001142767.2:c.730A>G NP_001136239.1:p.Thr244Ala missense NM_001142768.2:c.775A>G NP_001136240.1:p.Thr259Ala missense NM_001142769.3:c.856A>G NP_001136241.1:p.Thr286Ala missense NM_001142770.3:c.841A>G NP_001136242.1:p.Thr281Ala missense NM_001142771.2:c.856A>G NP_001136243.1:p.Thr286Ala missense NM_001142772.2:c.841A>G NP_001136244.1:p.Thr281Ala missense NM_001142773.2:c.775A>G NP_001136245.1:p.Thr259Ala missense NM_001354404.2:c.775A>G NP_001341333.1:p.Thr259Ala missense NM_001354411.2:c.841A>G NP_001341340.1:p.Thr281Ala missense NM_001354420.2:c.841A>G NP_001341349.1:p.Thr281Ala missense NM_001354429.2:c.841A>G NP_001341358.1:p.Thr281Ala missense NM_001354430.2:c.841A>G NP_001341359.1:p.Thr281Ala missense NC_000010.11:g.54317306T>C NC_000010.10:g.56077066T>C NG_009191.3:g.1316877A>G - Protein change
- T244A, T259A, T281A, T286A
- Other names
- NM_001384140.1(PCDH15):c.841A>G
- p.Thr281Ala
- Canonical SPDI
- NC_000010.11:54317305:T:C
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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
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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PCDH15 | - | - |
GRCh38 GRCh37 |
3319 | 3406 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Uncertain significance (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV001844739.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002545252.2 |
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
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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
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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
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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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Uncertain significance
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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Usher syndrome type 1F
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761085.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Thr281Ala variant in PCDH15 has been reported in 1 individual with Usher syndrome type 1F (PMID: 33090715) and has been identified in 0.02% (3/18384) … (more)
The p.Thr281Ala variant in PCDH15 has been reported in 1 individual with Usher syndrome type 1F (PMID: 33090715) and has been identified in 0.02% (3/18384) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs773843633). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 1343722) and has been interpreted as a variant of uncertain significance by Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr281Ala variant is uncertain. ACMG/AMP Criteria applied: BP4 (Richards 2015). (less)
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Uncertain significance
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002104028.2
First in ClinVar: Mar 12, 2022 Last updated: Oct 04, 2023 |
Comment:
Variant summary: PCDH15 c.841A>G (p.Thr281Ala) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Two of … (more)
Variant summary: PCDH15 c.841A>G (p.Thr281Ala) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251280 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.841A>G has been reported in the literature in individuals affected with autism spectrum disorders and retinitis pigmentosa (Ishizuka_2016, Liu_2020). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27058588, 33090715). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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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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Molecular diagnosis based on comprehensive genetic testing in 800 Chinese families with non-syndromic inherited retinal dystrophies. | Liu X | Clinical & experimental ophthalmology | 2021 | PMID: 33090715 |
Investigation of Rare Single-Nucleotide PCDH15 Variants in Schizophrenia and Autism Spectrum Disorders. | Ishizuka K | PloS one | 2016 | PMID: 27058588 |
Text-mined citations for rs773843633 ...
HelpRecord last updated Mar 30, 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.