ClinVar Miner

Submissions for variant NM_017780.4(CHD7):c.6775G>A (p.Ala2259Thr) (rs200806228)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000424210 SCV000512582 likely benign not specified 2016-10-31 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000696512 SCV000825075 uncertain significance CHARGE association 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2259 of the CHD7 protein (p.Ala2259Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant also falls at the last nucleotide of exon 31 of the CHD7 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs200806228, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with CHARGE syndrome (PMID: 22033296, 22539353, 22461308). ClinVar contains an entry for this variant (Variation ID: 377654). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics RCV000719920 SCV000850792 likely benign History of neurodevelopmental disorder 2018-12-07 criteria provided, single submitter clinical testing In silico models in agreement (benign);Does not segregate with disease in family study (genes with incomplete penetrance)
Illumina Clinical Services Laboratory,Illumina RCV001164558 SCV001326691 uncertain significance Hypogonadotropic hypogonadism 5 with or without anosmia 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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