ClinVar Miner

Submissions for variant NM_017780.4(CHD7):c.8366C>T (p.Ala2789Val) (rs376934539)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000177945 SCV000229908 uncertain significance not provided 2014-07-07 criteria provided, single submitter clinical testing
Invitae RCV000796515 SCV000936033 uncertain significance CHARGE association 2020-09-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 2789 of the CHD7 protein (p.Ala2789Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs376934539, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with Kallman syndrome (PMID: 23533228). ClinVar contains an entry for this variant (Variation ID: 197037). Experimental studies in a zebrafish model have shown that this missense change does not alter CHD7 function compared to wild type (PMID: 25472840). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000177945 SCV001552410 likely benign not provided no assertion criteria provided clinical testing The CHD7 p.Ala2789Val variant was identified in 1 of 438 proband chromosomes (frequency: 0.0023) from individuals or families with Kallmann Syndrome (Costa-Barbosa_2013_PMID:23533228). The variant was identified in dbSNP (ID: rs376934539) and ClinVar (classified as uncertain significance by Invitae and EGL Genetics). The variant was identified in control databases in 25 of 274676 chromosomes at a frequency of 0.00009102 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 4 of 7010 chromosomes (freq: 0.000571), African in 11 of 23378 chromosomes (freq: 0.000471), European (non-Finnish) in 8 of 125762 chromosomes (freq: 0.000064), European (Finnish) in 1 of 24348 chromosomes (freq: 0.000041) and South Asian in 1 of 29956 chromosomes (freq: 0.000033), but was not observed in the Latino, Ashkenazi Jewish, or East Asian populations. The p.Ala2789 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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