ClinVar Miner

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

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Total submissions: 7
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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

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