Variant summary: PHKA2 c.3614C>T (p.Pro1205Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 200197 control chromosomes (gnomAD). The variant, c.3614C>T, has been reported in the literature in multiple individuals both in heterozygote females and hemizygote males affected with Glycogen storage disease, type IXa1. Cho_2013 reports the variant in a female Chinese patient accompanied with a skewed X-chromosome inactivation, therefore, explaining the phenotypic representation in some females. Achouitar_2011 suggests the variant to be a Dutch founder mutation. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000292.3(PHKA2):c.3614C>T (p.Pro1205Leu)
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000292.3(PHKA2):c.3614C>T (p.Pro1205Leu)
Variation ID: 10531 Accession: VCV000010531.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp22.13 X: 18893579 (GRCh38) [ NCBI UCSC ] X: 18911697 (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 May 30, 2015 Oct 20, 2024 Sep 14, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000292.3:c.3614C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000283.1:p.Pro1205Leu missense NC_000023.11:g.18893579G>A NC_000023.10:g.18911697G>A NG_016622.1:g.95784C>T P46019:p.Pro1205Leu - Protein change
- P1205L
- Other names
- -
- Canonical SPDI
- NC_000023.11:18893578: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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Unknown function
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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.
- -
-
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. |
|||
| PHKA2 | - | - |
GRCh38 GRCh37 |
443 | 673 | |
| PHKA2-AS1 | - | - | - | GRCh38 | - | 132 |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 5, 2022 | RCV000011277.21 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 14, 2023 | RCV001091309.26 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jun 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease type VIII
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917993.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PHKA2 c.3614C>T (p.Pro1205Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: PHKA2 c.3614C>T (p.Pro1205Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 200197 control chromosomes (gnomAD). The variant, c.3614C>T, has been reported in the literature in multiple individuals both in heterozygote females and hemizygote males affected with Glycogen storage disease, type IXa1. Cho_2013 reports the variant in a female Chinese patient accompanied with a skewed X-chromosome inactivation, therefore, explaining the phenotypic representation in some females. Achouitar_2011 suggests the variant to be a Dutch founder mutation. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease IXa1
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001852724.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
A hemizygous missense variation in exon 33 of the PHKA2 gene that results in the amino acid substitution of Leucine for Proline at codon 1205 … (more)
A hemizygous missense variation in exon 33 of the PHKA2 gene that results in the amino acid substitution of Leucine for Proline at codon 1205 was detected. The observed variant c.3614C>T (p.Pro1205Leu) has not been reported in the 1000 genomes and gnomAD databases. The observed variant has previously been reported in multiple unrelated patients affected with glycogen storage disorders (Davit-Spraul et al 2011). The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Abdominal distention (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Indian
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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|
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Pathogenic
(Oct 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease IXa1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000940761.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 10531). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence … (more)
ClinVar contains an entry for this variant (Variation ID: 10531). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PHKA2 protein function. This missense change has been observed in individuals with glycogen storage disease or phosphorylase kinase (PHK) deficiency (PMID: 7847371, 9870210, 21646031, 21911307, 24055370, 25266922, 28468868). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1205 of the PHKA2 protein (p.Pro1205Leu). (less)
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|
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Pathogenic
(Apr 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease IXa1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018779.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Sep 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005324964.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
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: 34946936, 34134972, 35854365, 2303074, 25266922, 7847371, 22899091, 33834518, 31508908, 31248825, 10330341, Estrada2020[CaseReport], 30659246, 24055370, 21646031, 28468868, 9870210, 33763395, 34440436, 21911307) (less)
|
|
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Pathogenic
(May 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247263.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 4
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954283.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928255.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
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Pathogenic
(Feb 01, 1995)
|
no assertion criteria provided
Method: literature only
|
GLYCOGEN STORAGE DISEASE, TYPE IXa1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031505.4
First in ClinVar: Apr 04, 2013 Last updated: Apr 02, 2022 |
Comment on evidence:
In affected members of a large Dutch family with GSD type IXa1 (GSD9A1; 306000) previously described by Huijing and Fernandes (1969) and Willems et al. … (more)
In affected members of a large Dutch family with GSD type IXa1 (GSD9A1; 306000) previously described by Huijing and Fernandes (1969) and Willems et al. (1990), van den Berg et al. (1995) found a 3614C-T transition in the PHKA2 gene, resulting in a pro1205-to-leu (P1205L) substitution in a highly conserved region of the protein. (less)
|
Comment:
Comment:
A hemizygous missense variation in exon 33 of the PHKA2 gene that results in the amino acid substitution of Leucine for Proline at codon 1205 was detected. The observed variant c.3614C>T (p.Pro1205Leu) has not been reported in the 1000 genomes and gnomAD databases. The observed variant has previously been reported in multiple unrelated patients affected with glycogen storage disorders (Davit-Spraul et al 2011). The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Comment:
ClinVar contains an entry for this variant (Variation ID: 10531). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PHKA2 protein function. This missense change has been observed in individuals with glycogen storage disease or phosphorylase kinase (PHK) deficiency (PMID: 7847371, 9870210, 21646031, 21911307, 24055370, 25266922, 28468868). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1205 of the PHKA2 protein (p.Pro1205Leu).
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; This variant is associated with the following publications: (PMID: 34946936, 34134972, 35854365, 2303074, 25266922, 7847371, 22899091, 33834518, 31508908, 31248825, 10330341, Estrada2020[CaseReport], 30659246, 24055370, 21646031, 28468868, 9870210, 33763395, 34440436, 21911307)
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Unknown function
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001852724.1
|
|
Comment:
Variant summary: PHKA2 c.3614C>T (p.Pro1205Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 200197 control chromosomes (gnomAD). The variant, c.3614C>T, has been reported in the literature in multiple individuals both in heterozygote females and hemizygote males affected with Glycogen storage disease, type IXa1. Cho_2013 reports the variant in a female Chinese patient accompanied with a skewed X-chromosome inactivation, therefore, explaining the phenotypic representation in some females. Achouitar_2011 suggests the variant to be a Dutch founder mutation. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
A hemizygous missense variation in exon 33 of the PHKA2 gene that results in the amino acid substitution of Leucine for Proline at codon 1205 was detected. The observed variant c.3614C>T (p.Pro1205Leu) has not been reported in the 1000 genomes and gnomAD databases. The observed variant has previously been reported in multiple unrelated patients affected with glycogen storage disorders (Davit-Spraul et al 2011). The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Comment:
ClinVar contains an entry for this variant (Variation ID: 10531). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PHKA2 protein function. This missense change has been observed in individuals with glycogen storage disease or phosphorylase kinase (PHK) deficiency (PMID: 7847371, 9870210, 21646031, 21911307, 24055370, 25266922, 28468868). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1205 of the PHKA2 protein (p.Pro1205Leu).
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; This variant is associated with the following publications: (PMID: 34946936, 34134972, 35854365, 2303074, 25266922, 7847371, 22899091, 33834518, 31508908, 31248825, 10330341, Estrada2020[CaseReport], 30659246, 24055370, 21646031, 28468868, 9870210, 33763395, 34440436, 21911307)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing. | Ghosh A | Archives of disease in childhood | 2017 | PMID: 28468868 |
| The natural history of glycogen storage disease types VI and IX: Long-term outcome from the largest metabolic center in Canada. | Roscher A | Molecular genetics and metabolism | 2014 | PMID: 25266922 |
| X-linked glycogen storage disease IXa manifested in a female carrier due to skewed X chromosome inactivation. | Cho SY | Clinica chimica acta; international journal of clinical chemistry | 2013 | PMID: 24055370 |
| Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin. | Wang J | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22899091 |
| Common mutation in the PHKA2 gene with variable phenotype in patients with liver phosphorylase b kinase deficiency. | Achouitar S | Molecular genetics and metabolism | 2011 | PMID: 21911307 |
| Liver glycogen storage diseases due to phosphorylase system deficiencies: diagnosis thanks to non invasive blood enzymatic and molecular studies. | Davit-Spraul A | Molecular genetics and metabolism | 2011 | PMID: 21646031 |
| Mutational analyses in four Japanese families with X-linked liver phosphorylase kinase deficiency type 1. | Hirono H | Journal of inherited metabolic disease | 1998 | PMID: 9870210 |
| X-linked liver phosphorylase kinase deficiency is associated with mutations in the human liver phosphorylase kinase alpha subunit. | van den Berg IE | American journal of human genetics | 1995 | PMID: 7847371 |
| The natural history of liver glycogenosis due to phosphorylase kinase deficiency: a longitudinal study of 41 patients. | Willems PJ | European journal of pediatrics | 1990 | PMID: 2303074 |
| X-chromosomal inheritance of liver glycogenosis with phosphorylase kinase deficiency. | Huijing F | American journal of human genetics | 1969 | PMID: 5306139 |
Text-mined citations for rs137852288 ...
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 Oct 20, 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.