ClinVar Miner

Submissions for variant NM_017780.4(CHD7):c.694C>A (p.Pro232Thr) (rs554647169)

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Total submissions: 7
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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
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000258106 SCV000328316 benign CHARGE association 2016-09-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
Illumina Clinical Services Laboratory,Illumina RCV000258106 SCV000474377 likely benign CHARGE association 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000717586 SCV000848439 benign History of neurodevelopmental disorder 2016-08-27 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV000258106 SCV001010146 benign CHARGE association 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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