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

dbSNP: rs886039764

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000509012	SCV000267839	pathogenic	not provided	2022-11-25	criteria provided, single submitter	clinical testing	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)
Genomic Medicine Lab, University of California San Francisco	RCV000256185	SCV001572915	pathogenic	Intellectual disability, X-linked, syndromic, Bain type	2020-03-05	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000509012	SCV002011530	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000256185	SCV002556983	pathogenic	Intellectual disability, X-linked, syndromic, Bain type	2020-07-22	criteria provided, single submitter	clinical testing	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).
Laboratory of Medical Genetics, University of Torino	RCV000256185	SCV002760133	pathogenic	Intellectual disability, X-linked, syndromic, Bain type	2022-11-29	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000509012	SCV003917811	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	HNRNPH2: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP2, PP4
PreventionGenetics, part of Exact Sciences	RCV003401124	SCV004120001	pathogenic	HNRNPH2-related condition	2022-08-30	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000256185	SCV004183523	pathogenic	Intellectual disability, X-linked, syndromic, Bain type	2023-11-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000256185	SCV004236174	pathogenic	Intellectual disability, X-linked, syndromic, Bain type	2024-01-11	criteria provided, single submitter	clinical testing
OMIM	RCV000256185	SCV000322727	pathogenic	Intellectual disability, X-linked, syndromic, Bain type	2022-12-20	no assertion criteria provided	literature only
GenomeConnect - Simons Searchlight	RCV000256185	SCV001443368	likely pathogenic	Intellectual disability, X-linked, syndromic, Bain type	2018-03-16	no assertion criteria provided	provider interpretation	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.