ClinVar Miner

Submissions for variant NM_000345.4(SNCA):c.150T>G (p.His50Gln)

gnomAD frequency: 0.00007  dbSNP: rs201106962
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000344706 SCV000451646 uncertain significance Parkinson Disease, Dominant 2016-07-24 criteria provided, single submitter clinical testing The SNCA c.150T>G (His50Gln) missense variant has been reported in a heterozygous state in two individuals with Parkinson disease (Appel-Cresswell et al. 2013; Proukakis et al. 2014). Both individuals appeared to share a common haplotype, suggesting a possible founder effect. The p.His50Gln variant was absent from 1325 controls and is reported at a frequency of 0.00003 in the Total population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.His50Gln variant did not significantly alter the structure of the protein but accelerated SNCA fibril aggregation and oligomerization (Ghosh et al. 2013; Khalaf et al. 2014). The variant was also shown to increase SNCA secretion, extracellular toxicity, and cell death (Khalaf et al. 2014; Petrucci et al. 2015). Based on the collective evidence, the p.His50Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001301465 SCV001490635 uncertain significance Lewy body dementia; Autosomal dominant Parkinson disease 1 2023-11-25 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the SNCA protein (p.His50Gln). This variant is present in population databases (rs201106962, gnomAD 0.01%). This missense change has been observed in individual(s) with Parkinson's disease (PMID: 23427326, 23457019, 29398121). ClinVar contains an entry for this variant (Variation ID: 162095). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SNCA function (PMID: 23427326, 30528390). 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.
GeneDx RCV002307408 SCV002601357 uncertain significance not provided 2023-03-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect leading to accelerated protein aggregation (Ghosh et al., 2013; Porcari et al., 2015; Rutherford et al., 2014); Reported in patients with dopa-responsive Parkinson disease in published literature (Appel-Cresswell et al., 2013; Proukakis et al., 2013); Reported as a somatic variant in brain tissue of an individual with sporadic late-onset Parkinson disease (Proukakis et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26306801, 31980526, 29398121, 23669636, 26076669, 25330418, 26341711, 25554495, 24728187, 25505181, 24984882, 24936070, 25393002, 27573854, 30528390, 31996268, 23916651, 27250986, 23674458, 28650719, 24047453, 23674490, 23427326, 24315198, 23457019, 36099961)
Fulgent Genetics, Fulgent Genetics RCV002498683 SCV002782207 uncertain significance Lewy body dementia; Autosomal dominant Parkinson disease 1; Autosomal dominant Parkinson disease 4 2021-12-06 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV002307408 SCV004152975 uncertain significance not provided 2023-02-01 criteria provided, single submitter clinical testing SNCA: PS3:Supporting
OMIM RCV000149507 SCV000196158 pathogenic Autosomal dominant Parkinson disease 1 2014-08-08 no assertion criteria provided literature only

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