Submissions for variant NM_019597.5(HNRNPH2):c.616C>T (p.Arg206Trp) (rs886039763)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000509011	SCV000267838	pathogenic	not provided	2017-06-06	criteria provided, single submitter	clinical testing	The R206W variant in the HNRNPH2 gene has been reported previously as de novo in multiple female patients with developmental delay or intellectual disability, some of whom also exhibited regression, autism, seizures, or hypotonia (Bain et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R206W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same codon (R206Q) and a nearby residue (P209L) have also been reported in association with syndromic intellectual disability (Bain et al., 2016), supporting the functional importance of this region of the protein. We therefore interpret R206W as a pathogenic variant.
Institute of Human Genetics,Klinikum rechts der Isar	RCV000256179	SCV000680261	pathogenic	Mental retardation, X-linked, syndromic, Bain type	2017-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000623824	SCV000741250	likely pathogenic	Inborn genetic diseases	2016-08-18	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected
Mendelics	RCV000256179	SCV001141983	pathogenic	Mental retardation, X-linked, syndromic, Bain type	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000509011	SCV001245923	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV001195298	SCV001365617	pathogenic	Neurodevelopmental disorder	2019-06-05	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000256179	SCV000322726	pathogenic	Mental retardation, X-linked, syndromic, Bain type	2016-10-07	no assertion criteria provided	literature only