Submissions for variant NM_017780.4(CHD7):c.6194G>A (p.Arg2065His)

gnomAD frequency: 0.00001  dbSNP: rs1197494895

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001675988	SCV001894945	uncertain significance	not provided	2023-06-26	criteria provided, single submitter	clinical testing	Identified in a patient with congenital hypogonadotropic hypogonadism (CHH) with cryptorchidism, anosmia and delayed puberty (Goncalves et al., 2019); Reported as a variant of uncertain significance in an individual with microprenis and vanishing testes and no other features of CHARGE syndrome (Baxter et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25383892, 30733481, 21158681, 37305875)
Invitae	RCV001352688	SCV003440858	pathogenic	CHARGE association	2022-11-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg2065 amino acid residue in CHD7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23533228, 25064402, 25383892, 30733481). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHD7 protein function. This missense change has been observed in individuals with clinical features of CHD7-related conditions (PMID: 30733481; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2065 of the CHD7 protein (p.Arg2065His).
PreventionGenetics, part of Exact Sciences	RCV003416254	SCV004108018	uncertain significance	CHD7-related condition	2023-04-28	criteria provided, single submitter	clinical testing	The CHD7 c.6194G>A variant is predicted to result in the amino acid substitution p.Arg2065His. This variant has been reported in a male patient with micropenis and vanishing testes and no other features of CHARGE syndrome, and is classified as a variant of uncertain significance (Baxter et al 2015. PubMed ID: 25383892). This variant has also been reported in an individual with congenital hypogonadotropic hypogonadism and in a cohort of patients who underwent CHD7 mutation analysis (Gonçalves CI et al 2019. PubMed ID: 30733481; Bartels et al. 2010. PubMed ID: 21158681). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Alternative variants at the same amino acid (p.Arg2065Ser, p.Arg2065Gly, p.Arg2065Cys) have been reported in patients with CHARGE syndrome or Kallmann syndrome (Song et al. 2011. PubMed ID: 21931733; Costa-Barbosa FA et al 2013. PubMed ID: 23533228; Izumi Y et al 2014. PubMed ID: 25064402). However, for at least one variant p.Arg2065Gly, functional analysis showed it tested benign in zebrafish morphant rescue assay (Balasubramanian et al. 2014. PubMed ID: 25472840). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Laan Lab, Human Genetics Research Group, University of Tartu	RCV003991588	SCV004239187	likely pathogenic	Male infertility with spermatogenesis disorder	2023-09-01	criteria provided, single submitter	research
Laboratory of Medical Genetics, University of Torino	RCV001352688	SCV001547481	pathogenic	CHARGE association	2021-03-13	no assertion criteria provided	research