ClinVar Genomic variation as it relates to human health
NM_031263.4(HNRNPK):c.253G>A (p.Glu85Lys)
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.
Pathogenic(1); Likely pathogenic(4); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_031263.4(HNRNPK):c.253G>A (p.Glu85Lys)
Variation ID: 452520 Accession: VCV000452520.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q21.32 9: 83975466 (GRCh38) [ NCBI UCSC ] 9: 86590381 (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 Dec 19, 2017 Apr 15, 2024 Sep 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_031263.4:c.253G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_112553.1:p.Glu85Lys missense NM_001318186.2:c.253G>A NP_001305115.1:p.Glu85Lys missense NM_001318187.2:c.253G>A NP_001305116.1:p.Glu85Lys missense NM_001318188.2:c.253G>A NP_001305117.1:p.Glu85Lys missense NM_002140.5:c.253G>A NP_002131.2:p.Glu85Lys missense NM_031262.4:c.253G>A NP_112552.1:p.Glu85Lys missense NC_000009.12:g.83975466C>T NC_000009.11:g.86590381C>T NG_029577.1:g.10189G>A - Protein change
- E85K
- Other names
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- Canonical SPDI
- NC_000009.12:83975465: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
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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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HNRNPK | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
150 | 256 | |
HNRNPK-AS1 | - | - | - | GRCh38 | - | 89 |
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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2023 | RCV000522148.10 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Sep 1, 2022 | RCV000627090.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 1, 2018 | RCV001267488.2 |
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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Likely pathogenic
(Apr 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Au-Kline syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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The Genetics Institute, Rambam Health Care Campus
Accession: SCV000747834.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018 |
Comment:
This sequence change replaces Glutamic acid with Lysine at codon 85 of the HNRNPK protein p.(Glu85Lys). The glutamic acid residue is highly conserved and there … (more)
This sequence change replaces Glutamic acid with Lysine at codon 85 of the HNRNPK protein p.(Glu85Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (gmomAD, dbSNP,). This variant was found in an individual with clinical symptomes compatible with Au-Kline syndrome (MIM:616580 ), de novo inheritance was confirmed. ClinVar contains an entry for this variant (Variation ID: 452520). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). (less)
Clinical Features:
Intellectual disability (present) , Infantile muscular hypotonia (present) , Hip dysplasia (present)
Sex: female
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447542.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Cleft palate (present) , Atrial septal defect (present) , Global developmental delay (present)
Sex: female
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Uncertain significance
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Au-Kline syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572966.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.29; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as likely pathogenic and uncertain significance for HNRNPK -related disorder (ClinVar ID: VCV000452520). Threrefore, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Short stature (present) , Abnormal facial shape (present) , Hypotelorism (present) , Generalized hypotonia (present) , Long palpebral fissure (present) , Short columella (present) , … (more)
Short stature (present) , Abnormal facial shape (present) , Hypotelorism (present) , Generalized hypotonia (present) , Long palpebral fissure (present) , Short columella (present) , Hypothyroidism (present) , Progressive congenital scoliosis (present) , Atrial septal defect (present) , Intellectual disability (present) (less)
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Likely pathogenic
(Dec 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Au-Kline syndrome
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002578985.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Uncertain significance
(Mar 01, 2018)
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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: SCV001445669.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Heart murmur (present) , Large eyes (present) , Hip dislocation (present) , Cleft uvula (present) , Scoliosis (present) , Muscle weakness (present) , Cupped ear … (more)
Heart murmur (present) , Large eyes (present) , Hip dislocation (present) , Cleft uvula (present) , Scoliosis (present) , Muscle weakness (present) , Cupped ear (present) , Muscular hypotonia (present) , Flexion contracture (present) , Global developmental delay (present) , Ectropion of lower eyelids (present) , Gait disturbance (present) , Prominent fingertip pads (present) (less)
Sex: female
Ethnicity/Population group: Hispanic
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Pathogenic
(Sep 08, 2023)
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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: SCV000621333.3
First in ClinVar: Dec 19, 2017 Last updated: Sep 14, 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: 36130591, 33874999) (less)
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Likely pathogenic
(Sep 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004042360.5
First in ClinVar: Oct 14, 2023 Last updated: Apr 15, 2024 |
Comment:
HNRNPK: PS2, PM2, PS4:Moderate, PP2
Number of individuals with the variant: 1
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Pathogenic
(Nov 18, 2022)
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no assertion criteria provided
Method: literature only
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AU-KLINE SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002605170.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment on evidence:
In 5 unrelated patients with Au-Kline syndrome (AUKS; 616580), Choufani et al. (2022) identified a de novo heterozygous c.253G-A transition (c.253G-A, NM_002140.4) in exon 6 … (more)
In 5 unrelated patients with Au-Kline syndrome (AUKS; 616580), Choufani et al. (2022) identified a de novo heterozygous c.253G-A transition (c.253G-A, NM_002140.4) in exon 6 of the HNRNPK gene, resulting in a glu85-to-lys (E85K) substitution. In 3 patients who were tested, an intermediate AUKS-specific DNA methylation signature was identified in patient blood. (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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An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome. | Choufani S | American journal of human genetics | 2022 | PMID: 36130591 |
Text-mined citations for rs1554700678 ...
HelpRecord last updated Apr 15, 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.