ClinVar Genomic variation as it relates to human health
NM_019597.5(HNRNPH2):c.617G>A (p.Arg206Gln)
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_019597.5(HNRNPH2):c.617G>A (p.Arg206Gln)
Variation ID: 225761 Accession: VCV000225761.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101412605 (GRCh38) [ NCBI UCSC ] X: 100667593 (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 Oct 10, 2016 Aug 4, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_019597.5:c.617G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_062543.1:p.Arg206Gln missense NM_001032393.3:c.617G>A NP_001027565.1:p.Arg206Gln missense NM_001199973.2:c.*613G>A 3 prime UTR NM_001199974.2:c.*613G>A 3 prime UTR NC_000023.11:g.101412605G>A NC_000023.10:g.100667593G>A NG_007119.1:g.359C>T NG_016327.1:g.9403G>A LRG_672:g.359C>T P55795:p.Arg206Gln - Protein change
- R206Q
- Other names
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- Canonical SPDI
- NC_000023.11:101412604: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
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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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HNRNPH2 | - | - |
GRCh38 GRCh37 |
- | 205 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1284 |
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 (8) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000256185.16 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV000509012.15 | |
HNRNPH2-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Aug 30, 2022 | RCV003401124.4 |
Submissions - Germline
Classification
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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
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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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Pathogenic
(Mar 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked, syndromic, Bain type
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001572915.1 First in ClinVar: May 05, 2021 Last updated: May 05, 2021 |
Sex: female
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Pathogenic
(Nov 25, 2022)
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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: SCV000267839.4
First in ClinVar: Oct 07, 2017 Last updated: Dec 03, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34907471, 27545675, 29938792, 31164858, 30887513, 31236915, 31943778, 33504798, 33728377, 27535533) (less)
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Pathogenic
(Jul 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked, syndromic, Bain type
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556983.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
Comment:
PS2, PS4 – moderate, PM1, PM2, PP3 The HNRNPH2 c.617G>A variant is a single nucleotide change from a guanine to an adenine at position 617 … (more)
PS2, PS4 – moderate, PM1, PM2, PP3 The HNRNPH2 c.617G>A variant is a single nucleotide change from a guanine to an adenine at position 617 which is predicted to alter the amino acid arginine at position 206 in the protein to glutamine. The variant is de novo (both maternity and paternity confirmed) in a patient with the disease and no family history (PS2). The variant is in dbSNP (rs886039764) but is absent from population databases (PM2). This variant has been previously reported as de novo in a female patient with developmental delay, intellectual disability, and hypotonia, (PMID: 27545675) and more recently in similarly affected males (PMID: 30887513) (PS4 – moderate). The variant is located in exon 2 and this position is a mutational hotspot with other de novo variants reported at this position (e.g. Arg206Trp PMID: 27545675, PMID: 31236915; Arg206Leu PMID: 31943778) (PM1). The variant has been reported in ClinVar as Pathogenic by another diagnostic laboratory (Variation ID 225761). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
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Pathogenic
(Nov 29, 2022)
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criteria provided, single submitter
Method: research
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Intellectual disability, X-linked, syndromic, Bain type
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, University of Torino
Study: NeuroWES
Accession: SCV002760133.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
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Pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011530.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Aug 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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HNRNPH2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120001.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The HNRNPH2 c.617G>A variant is predicted to result in the amino acid substitution p.Arg206Gln. This variant has been previously reported as causative for X-linked HNRNPH2-related … (more)
The HNRNPH2 c.617G>A variant is predicted to result in the amino acid substitution p.Arg206Gln. This variant has been previously reported as causative for X-linked HNRNPH2-related neurodevelopmental disorder (Bain et al. 2016. PubMed ID: 27545675; Harmsen et al. 2019. PubMed ID: 30887513; Patient 071 in Demos et al. 2019. PubMed ID: 31164858; Martin et al. 2021. PubMed ID: 33504798, Supplementary Data 2; Bain et al. 2021. PubMed ID: 33728377). An alternate nucleotide change affecting the same amino acid (c.616C>T, p.Arg206Trp) has also been reported in individuals with HNRNPH2-related neurodevelopmental disorder (see for example Jepsen et al. 2019. PubMed ID: 31236915; Bain et al. 2021. PubMed ID: 33728377). In addition, this variant is interpreted as pathogenic or likely pathogenic by multiple laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/225761/). We therefore classify this variant as pathogenic. (less)
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Pathogenic
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked, syndromic, Bain type
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004183523.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked, syndromic, Bain type
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236174.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 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: SCV003917811.11
First in ClinVar: Apr 23, 2023 Last updated: Aug 04, 2024 |
Comment:
HNRNPH2: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP2, PP4
Number of individuals with the variant: 1
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Pathogenic
(Apr 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked, syndromic, Bain type
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005090970.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
Comment:
PS4, PM2, PM5, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 225761). This variant has been previously … (more)
PS4, PM2, PM5, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 225761). This variant has been previously reported as causative for X-linked HNRNPH2-related neurodevelopmental disorder (PMID:34907471). (less)
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Likely pathogenic
(Mar 16, 2018)
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no assertion criteria provided
Method: provider interpretation
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Intellectual disability, X-linked, syndromic, Bain type
Affected status: yes
Allele origin:
de novo
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GenomeConnect - Simons Searchlight
Accession: SCV001443368.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-03-16 and interpreted as Likely Pathogenic. The reporting … (more)
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-03-16 and interpreted as Likely Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Premature birth (present) , Strabismus (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Diarrhea (present) , Constipation (present) , … (more)
Autistic behavior (present) , Premature birth (present) , Strabismus (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Diarrhea (present) , Constipation (present) , Otitis media (present) , Abnormality of the skeletal system (present) , Scoliosis (present) , Abnormality of the skin (present) , Eczema (present) , Allergy (present) , Lactose intolerance (present) , Autoimmunity (present) , Vitiligo (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2015-10-23
Testing laboratory interpretation: Uncertain significance
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Feeding difficulties in infancy (present) , Clumsiness (present) , Generalized hypotonia (present) , Abnormality of the skin … (more)
Neonatal respiratory distress (present) , Hyperbilirubinemia (present) , Feeding difficulties in infancy (present) , Clumsiness (present) , Generalized hypotonia (present) , Abnormality of the skin (present) , Eczema (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: Hadassah The Women's Zionist Organization of America
Date variant was reported to submitter: 2015-01-26
Testing laboratory interpretation: not provided
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Pathogenic
(Dec 20, 2022)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, BAIN TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000322727.3
First in ClinVar: Oct 10, 2016 Last updated: Dec 24, 2022 |
Comment on evidence:
In a girl with the Bain type of X-linked syndromic intellectual developmental disorder (MRXSB; 300986), Bain et al. (2016) identified a de novo heterozygous c.617G-A … (more)
In a girl with the Bain type of X-linked syndromic intellectual developmental disorder (MRXSB; 300986), Bain et al. (2016) identified a de novo heterozygous c.617G-A transition (c.617G-A, NM_019597.4) in the HNRNPH2 gene, resulting in an arg206-to-gln (R206Q) substitution at a highly conserved residue in the nuclear localization sequence (NLS). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project database and was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but Bain et al. (2016) postulated a toxic gain-of-function effect. By whole-exome and Sanger sequencing in a boy with MRXSB, Jepsen et al. (2019) identified de novo hemizygosity for the R206Q mutation in the HNRNPH2 gene. The mutation was not present in his mother. In a brother and sister with MRXSB, who were born to consanguineous Indian parents, Somashekar et al. (2020) identified hemizygosity and heterozygosity for the R206Q mutation in the HNRNPH2 gene, respectively. Both parents were found to have the wildtype allele. The authors proposed that maternal germline mosaicism was the most likely explanation for occurrence in sibs. (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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Missense variants in the Arg206 residue of HNRNPH2: Further evidence of causality and expansion of the phenotype. | Peron A | American journal of medical genetics. Part A | 2020 | PMID: 31943778 |
Bain type of X-linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2. | Somashekar PH | American journal of medical genetics. Part A | 2020 | PMID: 31670473 |
Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2. | Jepsen WM | Clinical genetics | 2019 | PMID: 31236915 |
Bain type of X-linked syndromic mental retardation in boys. | Harmsen S | Clinical genetics | 2019 | PMID: 30887513 |
Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females. | Bain JM | American journal of human genetics | 2016 | PMID: 27545675 |
Text-mined citations for rs886039764 ...
HelpRecord last updated Sep 01, 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.