VCV002572476.1 - ClinVar

NM_015160.3(PMPCA):c.667C>T (p.Arg223Cys)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015160.3(PMPCA):c.667C>T (p.Arg223Cys)

Variation ID: 2572476 Accession: VCV002572476.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.3 9: 136416984 (GRCh38) [ NCBI UCSC ] 9: 139311436 (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	Jul 22, 2023	Jul 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015160.3:c.667C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055975.1:p.Arg223Cys	missense
NM_001282944.2:c.274C>T	NP_001269873.1:p.Arg92Cys	missense
NM_001282946.2:c.367C>T	NP_001269875.1:p.Arg123Cys	missense
NC_000009.12:g.136416984C>T
NC_000009.11:g.139311436C>T
NG_046789.1:g.11412C>T
NG_085291.1:g.1127C>T

... more HGVS ... less HGVS

Protein change

R123C, R223C, R92C

Other names

Canonical SPDI

NC_000009.12:136416983:C:T

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.

Links

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.
LOC126860792	-	-	-	GRCh38	-	85
PMPCA		-	-	GRCh38 GRCh37	142	274

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 recessive spinocerebellar ataxia 2	Uncertain significance (1)	criteria provided, single submitter	-	RCV003314361.1

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive spinocerebellar ataxia 2 Affected status: yes Allele origin: unknown	3billion Accession: SCV004013642.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 32369273 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.35; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMPCA related disorder (PMID: 32369273). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Developmental regression (present) , Atrophic superior cerebellar peduncle (present) , Axial hypotonia (present) , Truncal ataxia (present)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.35; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMPCA related disorder (PMID: 32369273). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline.

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
Consecutive medical exome analysis at a tertiary center: Diagnostic and health-economic outcomes.	Kosaki R	American journal of medical genetics. Part A	2020	PMID: 32369273

Text-mined citations for this variant ...

Record last updated Jul 22, 2023

ClinVar Genomic variation as it relates to human health

NM_015160.3(PMPCA):c.667C>T (p.Arg223Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...