Submissions for variant NM_017780.4(CHD7):c.8740G>A (p.Gly2914Arg)

gnomAD frequency: 0.00019  dbSNP: rs187751757

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000267205	SCV000474527	likely benign	Hypogonadotropic hypogonadism 5 with or without anosmia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV001753840	SCV000727577	benign	not provided	2021-09-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000359572	SCV000755771	likely benign	CHARGE syndrome	2025-01-15	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000359572	SCV000781114	likely benign	CHARGE syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317863	SCV000849891	likely benign	Inborn genetic diseases	2017-06-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055935	SCV005726056	likely benign	not specified	2024-11-21	criteria provided, single submitter	clinical testing	Variant summary: CHD7 c.8740G>A (p.Gly2914Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 245250 control chromosomes, with a total of 77 heterozygotes in gnomAD v2, this variant might be a benign change in CHD7-related diseases. c.8740G>A has been reported in the literature in individuals affected with Anterior hypospadia, without strong evidence for causality (Vuthy_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hypogonadotropic Hypogonadism 5 With Or Without Anosmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33468338). ClinVar contains an entry for this variant (Variation ID: 363486). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003972534	SCV004788331	likely benign	CHD7-related disorder	2021-09-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).