ClinVar Miner

Submissions for variant NM_002775.5(HTRA1):c.496C>T (p.Arg166Cys)

dbSNP: rs2097494390
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center RCV001785356 SCV002026365 likely pathogenic Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 2021-11-03 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS3_MOD, PS4_MOD, PM2_SUP, PP3
GeneDx RCV002291765 SCV002584477 likely pathogenic not provided 2022-10-07 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on protein activity and trimerization (Uemura et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27634960, 28402226, Santo_2019_Case Report, 36035189, 31316458, 32445900, 35946346, 33109952, 35699195, Yamashita_2019_Case Report, 30447605, 32719647, Zhang_2021_Case Report, 25712943)
Labcorp Genetics (formerly Invitae), Labcorp RCV002291765 SCV003441604 pathogenic not provided 2023-07-21 criteria provided, single submitter clinical testing 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 expected to disrupt HTRA1 protein function. Experimental studies have shown that this missense change affects HTRA1 function (PMID: 31316458). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1325819). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 166 of the HTRA1 protein (p.Arg166Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with HTRA1- related conditions (PMID: 25712943, 28402226, 30447605). It has also been observed to segregate with disease in related individuals.

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