The homozgous p.Arg192Ter variant was identified by our study in one individual with hypomyelinating leukodystrophy. This variant has been reported in 6 individuals with hypomyelinating leukodystrophy and microcephaly across 5 families (PMID: 27860360). Protein expression in skin fibroblasts from patients show absent protein. At least 5 other pathogenic loss of function have been reported in the literature and/or databases. In summary, the variant is pathogenic.
ClinVar Genomic variation as it relates to human health
NM_013328.4(PYCR2):c.796C>T (p.Arg266Ter)
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.
(5)
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.
Pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_013328.4(PYCR2):c.796C>T (p.Arg266Ter)
Variation ID: 254247 Accession: VCV000254247.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q42.12 1: 225921209 (GRCh38) [ NCBI UCSC ] 1: 226108909 (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 Sep 18, 2016 Feb 14, 2024 Sep 1, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_013328.4:c.796C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_037460.2:p.Arg266Ter nonsense NM_001271681.2:c.574C>T NP_001258610.1:p.Arg192Ter nonsense NC_000001.11:g.225921209G>A NC_000001.10:g.226108909G>A NG_044963.1:g.8132C>T - Protein change
- R266*, R192*
- Other names
- -
- Canonical SPDI
- NC_000001.11:225921208: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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. |
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| PYCR2 | - | - |
GRCh38 GRCh37 |
121 | 159 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV000240851.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 13, 2022 | RCV000578599.5 |
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
(-)
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criteria provided, single submitter
Method: research
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Hypomyelinating leukodystrophy 10
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Study: Broad Institute Center for Mendelian Genomics (CMG)
Accession: SCV000786714.1 First in ClinVar: Sep 18, 2016 Last updated: Sep 18, 2016 |
Comment:
The homozgous p.Arg192Ter variant was identified by our study in one individual with hypomyelinating leukodystrophy. This variant has been reported in 6 individuals with hypomyelinating … (more)
The homozgous p.Arg192Ter variant was identified by our study in one individual with hypomyelinating leukodystrophy. This variant has been reported in 6 individuals with hypomyelinating leukodystrophy and microcephaly across 5 families (PMID: 27860360). Protein expression in skin fibroblasts from patients show absent protein. At least 5 other pathogenic loss of function have been reported in the literature and/or databases. In summary, the variant is pathogenic. (less)
Number of individuals with the variant: 1
Clinical Features:
Abnormality of brain morphology (present)
Ethnicity/Population group: Unspecified
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Pathogenic
(Jan 02, 2019)
|
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: SCV000680916.2
First in ClinVar: Feb 13, 2018 Last updated: Apr 17, 2019 |
Comment:
The R266X variant in the PYCR2 gene has been reported previously in the homozygous state in multiple unrelated patients with microcephaly, failure to thrive, global … (more)
The R266X variant in the PYCR2 gene has been reported previously in the homozygous state in multiple unrelated patients with microcephaly, failure to thrive, global developmental delays, hypotonia, spasticity, dysmorphism, and hypomyelinating leukodystrophy (Zaki et al., 2016; Meng et al., 2017). This variant is predicted to cause loss of normal protein function through protein truncation, as 55 amino acid residues are lost. Protein expression studies performed on skin fibroblasts from patients with the homozygous R266X variant showed absence of the PYCR2 protein, while their heterozygous parents exhibited a reduction in PYCR2 protein levels (Zaki et al., 2016). The R266X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R266X as a pathogenic variant. (less)
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Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 10
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572601.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27130255). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000254247 / PMID: 27130255). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Epileptic spasm (present) , Global developmental delay (present)
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Pathogenic
(Jul 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003523499.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 254247). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 254247). This premature translational stop signal has been observed in individuals with clinical features of a hypomyelinating leukodystrophy (PMID: 27130255). 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 sequence change creates a premature translational stop signal (p.Arg266*) in the PYCR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the PYCR2 protein. (less)
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Pathogenic
(Sep 16, 2016)
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no assertion criteria provided
Method: literature only
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LEUKODYSTROPHY, HYPOMYELINATING, 10
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000299340.1
First in ClinVar: Sep 18, 2016 Last updated: Sep 18, 2016 |
Comment on evidence:
In 6 children from 5 unrelated Egyptian families with hypomyelinating leukodystrophy-10 (HLD10; 616420), Zaki et al. (2016) identified a homozygous c.796G-A transition (chr1.226,108,909G-A, GRCh37) in … (more)
In 6 children from 5 unrelated Egyptian families with hypomyelinating leukodystrophy-10 (HLD10; 616420), Zaki et al. (2016) identified a homozygous c.796G-A transition (chr1.226,108,909G-A, GRCh37) in the PYCR2 gene, resulting in an arg266-to-ter (R266X) substitution in the dimerization domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, 4 of which were consanguineous. The variant was filtered against the ExAC database and an in-house exome database of 5,000 individuals. Western blot analysis of 1 patient's fibroblasts showed absence of the protein, consistent with a complete loss of function. (less)
|
Comment:
Comment:
The R266X variant in the PYCR2 gene has been reported previously in the homozygous state in multiple unrelated patients with microcephaly, failure to thrive, global developmental delays, hypotonia, spasticity, dysmorphism, and hypomyelinating leukodystrophy (Zaki et al., 2016; Meng et al., 2017). This variant is predicted to cause loss of normal protein function through protein truncation, as 55 amino acid residues are lost. Protein expression studies performed on skin fibroblasts from patients with the homozygous R266X variant showed absence of the PYCR2 protein, while their heterozygous parents exhibited a reduction in PYCR2 protein levels (Zaki et al., 2016). The R266X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R266X as a pathogenic variant.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27130255). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000254247 / PMID: 27130255). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 254247). This premature translational stop signal has been observed in individuals with clinical features of a hypomyelinating leukodystrophy (PMID: 27130255). 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 sequence change creates a premature translational stop signal (p.Arg266*) in the PYCR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the PYCR2 protein.
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:
The homozgous p.Arg192Ter variant was identified by our study in one individual with hypomyelinating leukodystrophy. This variant has been reported in 6 individuals with hypomyelinating leukodystrophy and microcephaly across 5 families (PMID: 27860360). Protein expression in skin fibroblasts from patients show absent protein. At least 5 other pathogenic loss of function have been reported in the literature and/or databases. In summary, the variant is pathogenic.
Comment:
The R266X variant in the PYCR2 gene has been reported previously in the homozygous state in multiple unrelated patients with microcephaly, failure to thrive, global developmental delays, hypotonia, spasticity, dysmorphism, and hypomyelinating leukodystrophy (Zaki et al., 2016; Meng et al., 2017). This variant is predicted to cause loss of normal protein function through protein truncation, as 55 amino acid residues are lost. Protein expression studies performed on skin fibroblasts from patients with the homozygous R266X variant showed absence of the PYCR2 protein, while their heterozygous parents exhibited a reduction in PYCR2 protein levels (Zaki et al., 2016). The R266X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R266X as a pathogenic variant.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27130255). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000254247 / PMID: 27130255). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 254247). This premature translational stop signal has been observed in individuals with clinical features of a hypomyelinating leukodystrophy (PMID: 27130255). 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 sequence change creates a premature translational stop signal (p.Arg266*) in the PYCR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the PYCR2 protein.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy. | Meng L | American journal of medical genetics. Part A | 2017 | PMID: 27860360 |
| PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive. | Zaki MS | Annals of neurology | 2016 | PMID: 27130255 |
Text-mined citations for rs886037931 ...
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 Sep 29, 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.