ClinVar Miner

Submissions for variant NM_018026.4(PACS1):c.2281C>A (p.Pro761Thr)

gnomAD frequency: 0.00004  dbSNP: rs578033982
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
New York Genome Center RCV001420621 SCV001622945 uncertain significance Schuurs-Hoeijmakers syndrome 2020-06-11 criteria provided, single submitter clinical testing
GeneDx RCV001762678 SCV001999799 uncertain significance not provided 2019-12-10 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001420621 SCV003521118 uncertain significance Schuurs-Hoeijmakers syndrome 2023-10-10 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 761 of the PACS1 protein (p.Pro761Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PACS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1098662). 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 PACS1 protein function. 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 RCV002554091 SCV003741983 likely benign Inborn genetic diseases 2021-08-17 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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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