ClinVar Miner

Submissions for variant NM_017780.4(CHD7):c.8672A>G (p.Asn2891Ser) (rs202039728)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000177950 SCV000229913 likely benign not specified 2018-02-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000321183 SCV000474525 uncertain significance 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000273174 SCV000552234 uncertain significance CHARGE association 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2891 of the CHD7 protein (p.Asn2891Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs202039728, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with congenital diaphragmatic hernia (PMID: 25107291). ClinVar contains an entry for this variant (Variation ID: 197042). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000767108 SCV000589394 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing The N2891S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N2891S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N2891S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000718987 SCV000849851 likely benign History of neurodevelopmental disorder 2017-06-12 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000177950 SCV000966400 likely benign not specified 2019-01-04 criteria provided, single submitter clinical testing The p.Asn2891Ser variant in CHD7 is classified as likely benign because it has b een identified in 0.05% (18/35364) of Latino chromosomes by gnomAD (http://gnoma d.broadinstitute.org). ACMG/AMP criteria applied: BS1.

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