ClinVar Genomic variation as it relates to human health

PS2_VeryStrong, PM2

PS2, PM2, PS4

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.

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.

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)

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.

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.

PS1, PS2, PM1, PM2, PP2

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).

PM2, PM5, PP3, PP5

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.

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

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.

HNRNPH2: PM6:Very Strong, PM1, PM2, PM5, PS4:Moderate, PP2

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.