Submissions for variant NM_017780.4(CHD7):c.6193C>G (p.Arg2065Gly)

dbSNP: rs1064794250

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480035	SCV000568384	uncertain significance	not provided	2016-07-27	criteria provided, single submitter	clinical testing	The R2065G variant has been published previously in association with Kallmann syndrome (Costa-Barbosa et al., 2013). The variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R2065G 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. 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. However, functional studies in zebrafish have indicated that R2065G is a benign change with no effect on protein function (Balasubramanian et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001064858	SCV001229786	likely pathogenic	CHARGE association	2019-12-27	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with Kallmann syndrome (PMID: 23533228, 25472840). ClinVar contains an entry for this variant (Variation ID: 420036). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 2065 of the CHD7 protein (p.Arg2065Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant has been reported not to substantially affect CHD7 protein function (PMID: 25472840). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg2065 amino acid residue in CHD7. Other variant(s) that disrupt this residue have been observed in individuals with CHD7-related conditions (PMID: 25064402, 25383892, 30733481), which suggests that this may be a clinically significant amino acid residue.