VCV001285362.6 - ClinVar

NM_005055.5(RAPSN):c.491G>A (p.Arg164His)

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.

(3)

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
Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005055.5(RAPSN):c.491G>A (p.Arg164His)

Variation ID: 1285362 Accession: VCV001285362.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47447852 (GRCh38) [ NCBI UCSC ] 11: 47469404 (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	Mar 5, 2023	Sep 29, 2024	Feb 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005055.5:c.491G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005046.2:p.Arg164His	missense
NM_005055.4:c.491G>A
NM_032645.5:c.491G>A	NP_116034.2:p.Arg164His	missense
NC_000011.10:g.47447852C>T
NC_000011.9:g.47469404C>T
NG_008312.1:g.6327G>A

... more HGVS ... less HGVS

Protein change

R164H

Other names

Canonical SPDI

NC_000011.10:47447851: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.
RAPSN		-	-	GRCh38 GRCh37	679	693

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.
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Nov 8, 2023	RCV003132529.4
Fetal akinesia deformation sequence 2	Likely pathogenic (1)	criteria provided, single submitter	Feb 19, 2024	RCV003463061.2

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 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003813731.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely pathogenic (Feb 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fetal akinesia deformation sequence 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004206087.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Nov 08, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005324897.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Observed as a homozygous variant in multiple affected and unaffected relatives in a family with limb-girdle type congenital myasthenic syndrome. Affected patients also carried a … (more) Observed as a homozygous variant in multiple affected and unaffected relatives in a family with limb-girdle type congenital myasthenic syndrome. Affected patients also carried a homozygous variant in another gene, suggesting digenic inheritance with the R164H variant possibly being a hypomorphic allele (PMID: 27966543); Published functional studies suggest that this variant weakens the self-association of the protein and impairs end-plate acetylcholine receptor clustering (PMID: 34033754); Not observed at significant frequency in large population cohorts (gnomAD); Located within TPR5 domain (PMID: 22678886); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 34139178, 22678886, 27966543, 19620612, 34033754) (less)

Comment:

Observed as a homozygous variant in multiple affected and unaffected relatives in a family with limb-girdle type congenital myasthenic syndrome. Affected patients also carried a homozygous variant in another gene, suggesting digenic inheritance with the R164H variant possibly being a hypomorphic allele (PMID: 27966543); Published functional studies suggest that this variant weakens the self-association of the protein and impairs end-plate acetylcholine receptor clustering (PMID: 34033754); Not observed at significant frequency in large population cohorts (gnomAD); Located within TPR5 domain (PMID: 22678886); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 34139178, 22678886, 27966543, 19620612, 34033754)

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_005055.5(RAPSN):c.491G>A (p.Arg164His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...