ClinVar Genomic variation as it relates to human health
NM_001326411.2(PISD):c.899G>A (p.Cys300Tyr)
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_001326411.2(PISD):c.899G>A (p.Cys300Tyr)
Variation ID: 873551 Accession: VCV000873551.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.2 22: 31620659 (GRCh38) [ NCBI UCSC ] 22: 32016645 (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 May 31, 2020 Feb 4, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001326411.2:c.899G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001313340.1:p.Cys300Tyr missense NM_001326412.1:c.836G>A NP_001313341.1:p.Cys279Tyr missense NM_001326413.2:c.836G>A NP_001313342.1:p.Cys279Tyr missense NM_001326414.2:c.836G>A NP_001313343.1:p.Cys279Tyr missense NM_001326415.2:c.797G>A NP_001313344.1:p.Cys266Tyr missense NM_001326416.2:c.797G>A NP_001313345.1:p.Cys266Tyr missense NM_001326417.2:c.797G>A NP_001313346.1:p.Cys266Tyr missense NM_001326418.2:c.719G>A NP_001313347.1:p.Cys240Tyr missense NM_001326419.2:c.743-60G>A intron variant NM_001326420.2:c.665-60G>A intron variant NM_001326421.1:c.844+337G>A intron variant NM_014338.4:c.797G>A NP_055153.1:p.Cys266Tyr missense NM_178022.2:c.797G>A NP_821141.1:p.Cys266Tyr missense NC_000022.11:g.31620659C>T NC_000022.10:g.32016645C>T NG_050741.1:g.46906G>A - Protein change
- C266Y, C300Y, C240Y, C279Y
- Other names
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- Canonical SPDI
- NC_000022.11:31620658: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.
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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
Help
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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PISD | - | - |
GRCh38 GRCh37 |
152 | 194 |
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
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
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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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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- | RCV001095802.6 |
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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Liberfarb syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002053904.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Liberfarb syndrome
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072899.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.C300Y in PISD (NM_001326411.1) has been previously reported in affected patients and C266Y (Girisha KM et al; Zhao T et al).Functional analysis … (more)
The missense variant p.C300Y in PISD (NM_001326411.1) has been previously reported in affected patients and C266Y (Girisha KM et al; Zhao T et al).Functional analysis revealed a damaging effect. The p.C300Y variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.C300Y missense variant is predicted to be damaging by both SIFT and PolyPhen2. The cysteine residue at codon 300 of PISD is conserved in all mammalian species. The nucleotide c.899 in PISD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Failure to thrive (present) , Global developmental delay (present) , Hyperhidrosis (present) , Macrocephaly (present) , Sparse hair (present) , Sparse scalp hair (present) , … (more)
Failure to thrive (present) , Global developmental delay (present) , Hyperhidrosis (present) , Macrocephaly (present) , Sparse hair (present) , Sparse scalp hair (present) , Frontal bossing (present) , Low-set ears (present) , Blue sclerae (present) , Deeply set eye (present) , Smooth philtrum (present) , High palate (present) , Micrognathia (present) , Mesomelic/rhizomelic limb shortening (present) , Short stature (present) , Brachydactyly (present) , Clinodactyly (present) , Hematemesis (present) , Skeletal dysplasia (present) , Spondyloepimetaphyseal dysplasia (present) (less)
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Pathogenic
(May 20, 2020)
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no assertion criteria provided
Method: literature only
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LIBERFARB SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001251646.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment on evidence:
In an affected 3-year-old girl (P1) and 9-year-old boy (P2) from unrelated Indian families with Liberfarb syndrome (LIBF; 618889), Girisha et al. (2019) identified homozygosity … (more)
In an affected 3-year-old girl (P1) and 9-year-old boy (P2) from unrelated Indian families with Liberfarb syndrome (LIBF; 618889), Girisha et al. (2019) identified homozygosity for a c.797G-A transition (c.797G-A, NM_178022.1) in the PISD gene, resulting in a cys266-to-tyr (C266Y) substitution at a highly conserved residue. The unaffected parents were heterozygous for the mutation, which was not found in an in-house database of 475 control exomes from Indian families with rare mendelian disorders, or in the gnomAD database. Analysis of exome data and regions of homozygosity revealed that both probands shared a common haplotype around the PISD gene, indicating remote consanguinity. Patient-derived fibroblasts showed fragmented mitochondrial morphology around the nucleus compared to controls. Treatment of patient cells with MG-132 or staurosporine to induce activation of the intrinsic apoptosis pathway revealed significantly decreased cell viability with increased caspase-3 (CASP3; 600636) and caspase-7 (CASP7; 601761) activation. Ethanolamine supplementation largely restored cell viability and reduced CASP3/7 activation in MG-132-stressed patient cells. In transiently transfected HEK cells, Zhao et al. (2019) observed that the C266Y variant markedly reduced autocatalytic processing of the PISD protein, which is required for its activity. (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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PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes. | Zhao T | Life science alliance | 2019 | PMID: 30858161 |
The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function. | Girisha KM | Human mutation | 2019 | PMID: 30488656 |
Text-mined citations for rs2072505076 ...
HelpRecord last updated Apr 06, 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.