Submissions for variant NM_017780.4(CHD7):c.694C>A (p.Pro232Thr)

gnomAD frequency: 0.00002  dbSNP: rs554647169

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000194303	SCV000247030	likely benign	not specified	2015-07-20	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000258106	SCV000328316	benign	CHARGE syndrome	2016-09-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000297563	SCV000474376	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics	RCV002314796	SCV000848439	benign	Inborn genetic diseases	2016-08-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000258106	SCV001010146	benign	CHARGE syndrome	2025-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000194303	SCV001363293	likely benign	not specified	2019-03-04	criteria provided, single submitter	clinical testing	Variant summary: The variant, CHD7 c.694C>A (p.Pro232Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 246218 control chromosomes, predominantly at a frequency of 0.012 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9600 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHD7 causing Congenital Heart Disease phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.694C>A has been reported in the literature in an individual affected with Tetralogy of Fallot (DAlessandro_2016). However, this report does not provide unequivocal conclusions about association of the variant with Congenital Heart Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (X2) /likely benign (X2). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001568745	SCV001792670	likely benign	not provided	2021-03-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500588	SCV002803393	benign	CHARGE syndrome; Hypogonadotropic hypogonadism 5 with or without anosmia	2021-11-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001568745	SCV004155837	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	CHD7: BP4, BS1
PreventionGenetics, part of Exact Sciences	RCV003917743	SCV004734462	likely benign	CHD7-related disorder	2019-05-16	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).