ClinVar Miner

Submissions for variant NM_021116.4(ADCY1):c.2161A>G (p.Thr721Ala)

gnomAD frequency: 0.00045  dbSNP: rs74535389
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001329842 SCV001521385 uncertain significance Autosomal recessive nonsyndromic hearing loss 44 2019-06-07 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV001859267 SCV002177054 uncertain significance not provided 2023-11-18 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 721 of the ADCY1 protein (p.Thr721Ala). This variant is present in population databases (rs74535389, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ADCY1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1028721). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADCY1 protein function with a negative predictive value of 80%. 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 RCV002546354 SCV003679565 likely benign Inborn genetic diseases 2022-01-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.

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