VCV002579398.2 - ClinVar

NM_000965.5(RARB):c.1220T>C (p.Leu407Pro)

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.

(2)

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.

Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000965.5(RARB):c.1220T>C (p.Leu407Pro)

Variation ID: 2579398 Accession: VCV002579398.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.2 3: 25596489 (GRCh38) [ NCBI UCSC ] 3: 25637980 (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	Sep 16, 2023	Aug 11, 2024	Mar 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000965.5:c.1220T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000956.2:p.Leu407Pro	missense
NM_000965.3:c.1220T>C
NM_001290216.3:c.1241T>C	NP_001277145.1:p.Leu414Pro	missense
NM_001290217.2:c.884T>C	NP_001277146.1:p.Leu295Pro	missense
NM_001290266.2:c.1073T>C	NP_001277195.1:p.Leu358Pro	missense
NM_001290276.2:c.884T>C	NP_001277205.1:p.Leu295Pro	missense
NM_001290277.1:c.1082T>C	NP_001277206.1:p.Leu361Pro	missense
NM_001290300.2:c.1091T>C	NP_001277229.1:p.Leu364Pro	missense
NM_016152.4:c.884T>C	NP_057236.1:p.Leu295Pro	missense
NR_110892.2:n.1528T>C		non-coding transcript variant
NR_110893.2:n.1484T>C		non-coding transcript variant
NC_000003.12:g.25596489T>C
NC_000003.11:g.25637980T>C
NG_029013.3:g.772167T>C
NG_052961.1:g.72884A>G

... more HGVS ... less HGVS

Protein change

L295P, L358P, L361P, L364P, L407P, L414P

Other names

Canonical SPDI

NC_000003.12:25596488:T: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.

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.
RARB		-	-	GRCh38 GRCh37	111	136

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	Likely pathogenic (1)	criteria provided, single submitter	Mar 7, 2023	RCV003327833.1
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Mar 27, 2024	RCV004673873.1

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.
Likely pathogenic (Mar 07, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004034509.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
Likely pathogenic (Mar 27, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005163103.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (1) PubMed: 37092537 Comment: The c.1220T>C (p.L407P) alteration is located in exon 8 (coding exon 8) of the RARB gene. This alteration results from a T to C substitution … (more) The c.1220T>C (p.L407P) alteration is located in exon 8 (coding exon 8) of the RARB gene. This alteration results from a T to C substitution at nucleotide position 1220, causing the leucine (L) at amino acid position 407 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In an assay testing RARB function, this variant showed a functionally abnormal result (Caron, 2023). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Comment:

The c.1220T>C (p.L407P) alteration is located in exon 8 (coding exon 8) of the RARB gene. This alteration results from a T to C substitution at nucleotide position 1220, causing the leucine (L) at amino acid position 407 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In an assay testing RARB function, this variant showed a functionally abnormal result (Caron, 2023). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

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
Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.	Caron V	Genetics in medicine : official journal of the American College of Medical Genetics	2023	PMID: 37092537

Text-mined citations for this variant ...

Record last updated Aug 11, 2024

ClinVar Genomic variation as it relates to human health

NM_000965.5(RARB):c.1220T>C (p.Leu407Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...