rs886039763

Positions:

• chrX-101412604-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The ENST00000316594.6(HNRNPH2):​c.616C>T​(p.Arg206Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HNRNPH2 ENST00000316594.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31
• Conservation: PhyloP100: 2.63

Genes affected

HNRNPH2 (HGNC:5042): (heterogeneous nuclear ribonucleoprotein H2) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has three repeats of quasi-RRM domains that binds to RNAs. It is very similar to the family member HNRPH1. This gene is thought to be involved in Fabray disease and X-linked agammaglobulinemia phenotype. Alternative splicing results in multiple transcript variants encoding the same protein. Read-through transcription between this locus and the ribosomal protein L36a gene has been observed. [provided by RefSeq, Jan 2011]

RPL36A-HNRNPH2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000316594.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101412605-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225761.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=11, Uncertain_significance=1}.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HNRNPH2. . Gene score misZ 3.6248 (greater than the threshold 3.09). GenCC has associacion of gene with intellectual disability, X-linked, syndromic, Bain type.
• PP5: Variant X-101412604-C-T is Pathogenic according to our data. Variant chrX-101412604-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101412604-C-T is described in Lovd as [Pathogenic]. Variant chrX-101412604-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPH2	NM_019597.5	c.616C>T	p.Arg206Trp	missense_variant	2/2	ENST00000316594.6	NP_062543.1
RPL36A-HNRNPH2	NM_001199973.2	c.*612C>T		3_prime_UTR_variant	5/5		NP_001186902.2
HNRNPH2	NM_001032393.3	c.616C>T	p.Arg206Trp	missense_variant	2/2		NP_001027565.1
RPL36A-HNRNPH2	NM_001199974.2	c.*612C>T		3_prime_UTR_variant	4/4		NP_001186903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPH2	ENST00000316594.6	c.616C>T	p.Arg206Trp	missense_variant	2/2	1	NM_019597.5	ENSP00000361927	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:31

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked, syndromic, Bain type Pathogenic:19

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2022	Variant summary: HNRNPH2 c.616C>T (p.Arg206Trp) results in a non-conservative amino acid change located in the glycine-rich domain (Bain_2016) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 183420 control chromosomes (gnomAD). c.616C>T has been reported in the literature in multiple individuals affected with Neurodevelopmental disorder (Bain_2016, Jepsen_2019, Martin_2021) and identified as de novo mutation. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fifteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0110 - This gene is known to be associated with X-linked dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan (exon2). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (missense hotpost within the nuclear localization sequence; PMID: 27545675). (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a glutamine has also been reported as pathogenic (ClinVar, PMID: 27545675, 30887513). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple patients (ClinVar, PMID: 27545675, 31236915). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Oct 22, 2020	The varinat c.616C>T (p.Arg206Trp) in the HNRNPH2 gene is reported as pathogenic/likely pathogenic for Bain type of X-linked syndromic mental retardation in ClinVar (Variation ID: 225760) and as pathogenic in the Global Variome shared LOVD database v.3.0. There is no information on frequency in gnomAD, 1000 Genomes or NHLI Exome Sequencing Project (ESP). This variant has been reported as pathogenic by Somashekar et al., 2019 (PMID: 31670473) and Bain et al., 2016 (PMID: 27545675). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM2, PM5, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	PS1, PS2, PM1, PM2, PP2 -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Nov 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 20, 2021	PS2, PM2, PS4 -
Pathogenic, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.616C>T (p.Arg206Trp) variant in HNRNPH2 has been reported as de novo by whole exome sequencing in 19 individuals with a neurodevelopmental disorder consisting of developmental delay and variable presentation of regression, autism, tone abnormalities, seizures and/or psychiatric co-morbidities such as ADHD, anxiety, and OCD (Bain et al. 2019). The amino acid Arg at position 206 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The p.Arg206Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely pathogenic. The variant occurs in a region of the protein that is critical for protein function and has been frequently altered in diseased individuals (Van Dusen et al. 2010). The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Arg206Trp in HNRNPH2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 01, 2020	PS2_VeryStrong, PM2 -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Apr 18, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-18 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 18, 2022	This HNRNPH2 variant (rs886039763) is absent from a large population dataset and has been reported in ClinVar. It is the most frequent, recurrent de novo variant identified in individuals with X-linked HNRNPH2-related neurodevelopmental disorder. In addition, another pathogenic missense variant affecting the same codon (p.Arg206Gln) has been reported. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while another predicts that it would be tolerated. The arginine residue at this position is evolutionarily conserved across most vertebrate species assessed. This variant is not predicted to affect normal exon 2 splicing, although this has not been confirmed experimentally to our knowledge. We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 09, 2022	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2022	Not observed 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: 27545675, 29938792, 31236915, 31670473, 34008892, 33504798, 33739554, 33728377) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics laboratory, Necker Hospital	Mar 24, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	HNRNPH2: PM6:Very Strong, PM1, PM2, PM5, PS4:Moderate, PP2 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 15, 2022	The HNRNPH2 c.616C>T (p.Arg206Trp) missense variant results in the substitution of arginine at amino acid position 206 with tryptophan. The p.Arg206Trp variant is a recurrent variant which has been reported in a heterozygous state in over 20 unrelated individuals with neurodevelopmental phenotypes (PMID: 27545675; PMID: 31236915; PMID: 31670473; PMID: 33728377; PMID: 34008892). At least three different missense variants at Arg206 have also been identified in over ten affected individuals, suggesting that Arg206 is a hotspot for disease-causing variation (PMID:30887513; PMID: 33728377; PMID: 33504798). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The p.Arg206Trp variant is found in a well conserved nuclear localization sequence in a glycine rich domain (PMID: 33728377). Functional studies are unavailable for p.Arg206Trp, but cellular localization studies performed on another variant at Arg206, p.Arg206Gln, showed altered cellular localization patterns compared to wild type, which were suggestive of a nucleocytoplasmic shuttling defect (PMID: 34907471). Based on the available evidence, the c.616C>T p.(Arg206Trp) variant is classified as pathogenic for HNRNPH2-related neurodevelopmental disorder. -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

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Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.616C>T (p.R206W) alteration is located in exon 2 (coding exon 1) of the HNRNPH2 gene. This alteration results from a C to T substitution at nucleotide position 616, causing the arginine (R) at amino acid position 206 to be replaced by a tryptophan (W). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the HNRNPH2 c.616C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was reported as a de novo occurrence in multiple patients, both male and female, presenting with Bain-type syndromic intellectual disabiltiy which also included autism/behavioral disturbances, hypotonia, ataxia with gait abnormalities, seizures, and dysmorphic features (Bain, 2016; Jepsen, 2019; Somashekar, 2020). In addition, alterations at the same codon (p.R206Q and p.R206L) were reported de novo in three additional patients with a similar phenotype including developmental delay, intellectual disability, regression, and hypotonia, suggesting that the R206 amino acid is a mutational hotspot (Bain, 2016; Harmsen, 2019; Peron, 2020). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R206 amino acid is conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.R206W alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Stereotypic movement disorder;C0424503:Abnormal facial shape Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

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Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 05, 2019

The c.616C>T (p.Arg206Trp) variant in HNRNPH2 has been reported as de novo by whole exome sequencing in 19 individuals with a neurodevelopmental disorder consisting of developmental delay and variable presentation of regression, autism, tone abnormalities, seizures and/or psychiatric co-morbidities such as ADHD, anxiety, and OCD (Bain et al. 2019). It was absent from large population studies and has been reported in ClinVar (Variation ID 225760). Additionally, another missense variant at this same codon, p.Arg206Gln, has also been reported as de novo in at least two individuals with a neurodevelopmental disorder (Bain et al. 2019, Harmsen et al. 2019) and has been reported in ClinVar (Variation ID 225761). The majority of affected individuals are female. The variant occurs in a region of the protein that is critical for protein function and has been frequently altered in diseased individuals (Van Dusen et al. 2010, Bain et al. 2019). Lastly, computational prediction tools and conservation analysis support that the variant impacts protein function. In summary, this variant meets criteria to be classified as pathogenic for neurodevelopmental disorder in an X-linked dominant manner based upon case counts, de novo occurrence, a different pathogenic missense at the same position, and location at a critical residue, and predicted impact on protein. ACMG/AMP Criteria applied: PS2_VeryStrong, PM2, PM5, PM1, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.18
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.059	T
Polyphen		0.028	B
Vest4		0.75
MutPred		0.46		Loss of disorder (P = 8e-04);
MVP		0.93
MPC		1.6
ClinPred		0.97	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886039763; hg19: chrX-100667592; COSMIC: COSV54509419; COSMIC: COSV54509419;