VCV000162095.27 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 162095 Accession: VCV000162095.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q22.1 4: 89828156 (GRCh38) [ NCBI UCSC ] 4: 90749307 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Nov 24, 2024	Nov 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000345.4:c.150T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000336.1:p.His50Gln	missense
NM_001146054.2:c.150T>G	NP_001139526.1:p.His50Gln	missense
NM_001146055.2:c.150T>G	NP_001139527.1:p.His50Gln	missense
NM_001375285.1:c.150T>G	NP_001362214.1:p.His50Gln	missense
NM_001375286.1:c.150T>G	NP_001362215.1:p.His50Gln	missense
NM_001375287.1:c.150T>G	NP_001362216.1:p.His50Gln	missense
NM_001375288.1:c.150T>G	NP_001362217.1:p.His50Gln	missense
NM_007308.3:c.150T>G	NP_009292.1:p.His50Gln	missense
NR_164674.1:n.228T>G		non-coding transcript variant
NR_164675.1:n.375T>G		non-coding transcript variant
NR_164676.1:n.448T>G		non-coding transcript variant
NC_000004.12:g.89828156A>C
NC_000004.11:g.90749307A>C
NG_011851.1:g.15141T>G
	P37840:p.His50Gln

... more HGVS ... less HGVS

Protein change

H50Q

Other names

Canonical SPDI

NC_000004.12:89828155:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00008

Links

ClinGen: CA273048 UniProtKB: P37840#VAR_070171 OMIM: 163890.0007 dbSNP: rs201106962 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SNCA		-	-	GRCh38 GRCh37	166	206

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal dominant Parkinson disease 1	Pathogenic (1)	no assertion criteria provided	Aug 8, 2014	RCV000149507.9
Parkinson Disease, Dominant	Uncertain significance (1)	criteria provided, single submitter	Jul 24, 2016	RCV000344706.6
Autosomal dominant Parkinson disease 1 Autosomal dominant Parkinson disease 4 Lewy body dementia	Uncertain significance (1)	criteria provided, single submitter	Dec 6, 2021	RCV002498683.1
Autosomal dominant Parkinson disease 1 Lewy body dementia	Uncertain significance (1)	criteria provided, single submitter	Nov 25, 2023	RCV001301465.8
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Sep 27, 2023	RCV002307408.14

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Dec 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lewy body dementia Autosomal dominant Parkinson disease 1 Autosomal dominant Parkinson disease 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002782207.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Mar 23, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002601357.3 First in ClinVar: Nov 19, 2022 Last updated: Apr 15, 2023	Comment: 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 … (more) 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) (less)
Uncertain significance (Nov 25, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Lewy body dementia Autosomal dominant Parkinson disease 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001490635.4 First in ClinVar: Mar 07, 2021 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 23427326‚ 23457019‚ 29398121‚ 30528390 Comment: 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). … (more) 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. (less)
Uncertain significance (Sep 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005410564.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (14) PubMed: 23427326‚ 23457019‚ 23669636‚ 24047453‚ 24936070‚ 24984882‚ 25393002‚ 25505181‚ 26076669‚ 27573854‚ 29398121‚ 30528390‚ 31980526‚ 31996268 Comment: BS2, PS3, PS4_moderate Number of individuals with the variant: 1
Uncertain significance (Jul 24, 2016)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Parkinson Disease, Dominant Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000451646.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (5) PubMed: 24047453‚ 23427326‚ 23457019‚ 24936070‚ 26341711 Comment: 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 … (more) 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. (less)
Uncertain significance (Feb 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004152975.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: SNCA: PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Aug 08, 2014)	no assertion criteria provided Method: literature only	PARKINSON DISEASE 1, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000196158.6 First in ClinVar: Dec 26, 2014 Last updated: Jul 08, 2022	Publications: PubMed (2) PubMed: 23427326‚ 24936070 Comment on evidence: In a Caucasian English woman with PARK1 (168601), Proukakis et al. (2013) identified a heterozygous c.150T-G transversion in exon 3 of the SNCA gene, resulting … (more) In a Caucasian English woman with PARK1 (168601), Proukakis et al. (2013) identified a heterozygous c.150T-G transversion in exon 3 of the SNCA gene, resulting in a his50-to-gln (H50Q) substitution at a conserved residue in a copper-binding region. The mutation, which was found by direct sequencing of the SNCA gene, was not present in the 1000 Genomes Project database or in 450 control DNA samples. Electron paramagnetic resonance studies indicated that the mutant residue was able to bind copper, but in contrast to wildtype, there was no participation in metal coordination from other portions of the protein. The patient developed PD at age 71, became forgetful at 80, and died at 83. Autopsy confirmed PD, with loss of pigmented cells in the substantia nigra and presence of Lewy bodies; plaques and neurofibrillary tangles were also noted in the cortex and hippocampus. There was no family history of a similar disorder. In vitro studies by Khalaf et al. (2014) indicated that the H50Q mutation did not significantly perturb the overall shape, size, or structure of the protein compared to wildtype, but the mutation accelerated SNCA fibril aggregation and oligomerization. Cell-based studies showed that H50Q increased SNCA secretion from cells into the culture medium, induced neuronal cell death when added to the culture medium, and increased mitochondrial fragmentation in mouse hippocampal neurons. The findings suggested that the H50Q mutant may cause extracellular toxicity. (less)

Comment:

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)

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies.	Orme T	Acta neuropathologica communications	2020	PMID: 31996268
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
Biochemical and morphological classification of disease-associated alpha-synuclein mutants aggregates.	Tanaka G	Biochemical and biophysical research communications	2019	PMID: 30528390
Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease.	Blauwendraat C	Neurobiology of aging	2018	PMID: 29398121
Mutations associated with familial Parkinson's disease alter the initiation and amplification steps of α-synuclein aggregation.	Flagmeier P	Proceedings of the National Academy of Sciences of the United States of America	2016	PMID: 27573854
Phenotypic spectrum of alpha-synuclein mutations: New insights from patients and cellular models.	Petrucci S	Parkinsonism & related disorders	2016	PMID: 26341711
Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation.	Dettmer U	Nature communications	2015	PMID: 26076669
The H50Q mutation induces a 10-fold decrease in the solubility of α-synuclein.	Porcari R	The Journal of biological chemistry	2015	PMID: 25505181
Systematic comparison of the effects of alpha-synuclein mutations on its oligomerization and aggregation.	Lázaro DF	PLoS genetics	2014	PMID: 25393002
Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein.	Rutherford NJ	Journal of neurochemistry	2014	PMID: 24984882
The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity.	Khalaf O	The Journal of biological chemistry	2014	PMID: 24936070
The Parkinson's disease-associated H50Q mutation accelerates α-Synuclein aggregation in vitro.	Ghosh D	Biochemistry	2013	PMID: 24047453
α-Synuclein mutations cluster around a putative protein loop.	Kara E	Neuroscience letters	2013	PMID: 23669636
Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease.	Appel-Cresswell S	Movement disorders : official journal of the Movement Disorder Society	2013	PMID: 23457019
A novel α-synuclein missense mutation in Parkinson disease.	Proukakis C	Neurology	2013	PMID: 23427326
click to load more click to collapse

Text-mined citations for rs201106962 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201106962 ...