VCV000018458.30 - ClinVar

NM_024411.5(PDYN):c.414G>T (p.Arg138Ser)

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.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(2); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024411.5(PDYN):c.414G>T (p.Arg138Ser)

Variation ID: 18458 Accession: VCV000018458.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20p13 20: 1980674 (GRCh38) [ NCBI UCSC ] 20: 1961320 (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	Apr 4, 2013	Oct 20, 2024	Sep 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_024411.5:c.414G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_077722.1:p.Arg138Ser	missense
NM_001190892.1:c.414G>T	NP_001177821.1:p.Arg138Ser	missense
NM_001190898.3:c.414G>T	NP_001177827.1:p.Arg138Ser	missense
NM_001190899.2:c.414G>T	NP_001177828.1:p.Arg138Ser	missense
NM_001190900.1:c.414G>T	NP_001177829.1:p.Arg138Ser	missense
NC_000020.11:g.1980674C>A
NC_000020.10:g.1961320C>A
NG_028027.1:g.18572G>T
LRG_667:g.18572G>T
LRG_667t1:c.414G>T	LRG_667p1:p.Arg138Ser
	P01213:p.Arg138Ser

... more HGVS ... less HGVS

Protein change

R138S

Other names

Canonical SPDI

NC_000020.11:1980673:C:A

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) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00008

Links

ClinGen: CA257551 UniProtKB: P01213#VAR_064913 OMIM: 131340.0001 dbSNP: rs267606941 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.
PDYN		-	-	GRCh38 GRCh37	2	222
PDYN-AS1	-	-	-	GRCh38	-	199

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.
Spinocerebellar ataxia type 23	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Sep 29, 2023	RCV000018094.34
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Sep 21, 2023	RCV001268483.27

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 (Sep 29, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Spinocerebellar ataxia type 23 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001142168.2 First in ClinVar: Jan 10, 2020 Last updated: Oct 04, 2023
Pathogenic (Jul 30, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003262120.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 21035104‚ 22287014‚ 23355175 Comment: This missense change has been observed in individual(s) with clinical features of spinocerebellar ataxia (PMID: 21035104, 22287014, 23355175). It has also been observed to segregate … (more) This missense change has been observed in individual(s) with clinical features of spinocerebellar ataxia (PMID: 21035104, 22287014, 23355175). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs267606941, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 138 of the PDYN protein (p.Arg138Ser). ClinVar contains an entry for this variant (Variation ID: 18458). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters PDYN gene expression (PMID: 21035104). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447446.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Polyneuropathy (present) , Gait disturbance (present) Sex: male
Uncertain significance (Sep 21, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002584237.3 First in ClinVar: Oct 22, 2022 Last updated: Sep 30, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 21035104)
Likely pathogenic (May 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia type 23 Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV004042773.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: ACMG criteria used to clasify this variant: PS4, PS3_MOD, PP1 Clinical Features: Cerebellar ataxia (present)
Likely pathogenic (Oct 01, 2021)	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: SCV002064033.20 First in ClinVar: Jan 29, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Nov 12, 2010)	no assertion criteria provided Method: literature only	SPINOCEREBELLAR ATAXIA 23 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038373.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 21035104 Comment on evidence: In affected members of a Dutch family with autosomal dominant spinocerebellar ataxia-23 (SCA23; 610245), Bakalkin et al. (2010) identified a heterozygous 414G-T transversion in exon … (more) In affected members of a Dutch family with autosomal dominant spinocerebellar ataxia-23 (SCA23; 610245), Bakalkin et al. (2010) identified a heterozygous 414G-T transversion in exon 4 of the PDYN gene, resulting in an arg138-to-ser (R138S) substitution in a nonconserved residue of the nonopioid domain. The mutation was not found in 1,000 control chromosomes. The age at onset ranged from 43 to 56 years, and the disorder was characterized by slowly progressive gait and limb ataxia, variable dysarthria, slow saccades, ocular dysmetria, and decreased vibratory sense below the knees. Four affected individuals showed hyperreflexia, 2 of whom also had extensor plantar responses. Postmortem examination of 1 patient showed severe cerebellar atrophy. Immunohistochemical studies of cerebellum derived from 1 patient with the R138S mutation showed that PDYN, dynorphin A, and dynorphin B were located in Purkinje cells as observed in control cerebellum, but cerebellar tissue with the mutation had decreased levels of EAAT4 (SLC1A6; 600636) and calbindin (CALB1; 114050), both of which are markers of Purkinje cells. SLC1A6 was accumulated and aggregated in patient cerebellar tissue. These changes in SLC1A6 suggested a defect in glutamate signaling. (less)

Comment:

This missense change has been observed in individual(s) with clinical features of spinocerebellar ataxia (PMID: 21035104, 22287014, 23355175). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs267606941, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 138 of the PDYN protein (p.Arg138Ser). ClinVar contains an entry for this variant (Variation ID: 18458). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters PDYN gene expression (PMID: 21035104). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0").

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
Mutations in PDYN are not responsible for multiple system atrophy.	Fogel BL	Journal of neurology	2013	PMID: 23355175
Mutations in rare ataxia genes are uncommon causes of sporadic cerebellar ataxia.	Fogel BL	Movement disorders : official journal of the Movement Disorder Society	2012	PMID: 22287014
Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23.	Bakalkin G	American journal of human genetics	2010	PMID: 21035104

Text-mined citations for rs267606941 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_024411.5(PDYN):c.414G>T (p.Arg138Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267606941 ...