VCV000225761.29 - ClinVar

NM_019597.5(HNRNPH2):c.617G>A (p.Arg206Gln)

Germline

Classification

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.

(13)

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.

Conflicting classifications of pathogenicity
Pathogenic(10); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_019597.5(HNRNPH2):c.617G>A (p.Arg206Gln)

Variation ID: 225761 Accession: VCV000225761.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.1 X: 101412605 (GRCh38) [ NCBI UCSC ] X: 100667593 (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	Oct 10, 2016	Oct 20, 2024	Jan 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

R206Q

Other names

Canonical SPDI

NC_000023.11:101412604:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA10576092 UniProtKB: P55795#VAR_077233 OMIM: 300610.0002 dbSNP: rs886039764 VarSome

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
Gene	OMIM	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.
HNRNPH2		-	-	GRCh38 GRCh37	3	215
RPL36A-HNRNPH2	-	-	-	GRCh38 GRCh37	-	1295

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.
Intellectual disability, X-linked, syndromic, Bain type	Conflicting interpretations of pathogenicity (9)	criteria provided, conflicting classifications	Jan 11, 2024	RCV000256185.17
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 1, 2023	RCV000509012.17
HNRNPH2-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 30, 2022	RCV003401124.4

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.
Pathogenic (Nov 25, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	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)
Pathogenic (Jul 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked, syndromic, Bain type Affected status: yes Allele origin: germline	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	Publications: PubMed (4) PubMed: 27545675‚ 30887513‚ 31236915‚ 31943778 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)
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	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
Pathogenic (Nov 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked, syndromic, Bain type Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004183523.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Mar 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked, syndromic, Bain type (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	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
Pathogenic (Nov 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual disability, X-linked, syndromic, Bain type Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, University of Torino Study: NeuroWES Accession: SCV002760133.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022
Pathogenic (Aug 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HNRNPH2-related condition Affected status: unknown Allele origin: germline	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)
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked, syndromic, Bain type Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004236174.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Apr 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked, syndromic, Bain type Affected status: yes Allele origin: germline	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)
Uncertain significance (Jun 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked, syndromic, Bain type (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005373591.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: The observed missense c.647C>T(p.Ser216Leu) variant in LGI1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. … (more) The observed missense c.647C>T(p.Ser216Leu) variant in LGI1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser216Leu variant is present with allele frequency of 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid of p.Ser216Leu in LGI1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 216 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). (less) Clinical Features: Abnormality of the nervous system (present)
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003917811.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: HNRNPH2: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP2, PP4 Number of individuals with the variant: 1
Pathogenic (Dec 20, 2022)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, BAIN TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000322727.3 First in ClinVar: Oct 10, 2016 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 27545675‚ 31236915‚ 31670473 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)
Likely pathogenic (Mar 16, 2018)	no assertion criteria provided Method: provider interpretation	Intellectual disability, X-linked, syndromic, Bain type Affected status: yes Allele origin: de novo	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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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 is associated with the following publications: (PMID: 34907471, 27545675, 29938792, 31164858, 30887513, 31236915, 31943778, 33504798, 33728377, 27535533)

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 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).

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 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.

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 reported as causative for X-linked HNRNPH2-related neurodevelopmental disorder (PMID:34907471).

Comment:

The observed missense c.647C>T(p.Ser216Leu) variant in LGI1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser216Leu variant is present with allele frequency of 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid of p.Ser216Leu in LGI1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 216 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).

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 laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_019597.5(HNRNPH2):c.617G>A (p.Arg206Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886039764 ...