VCV000099766.35 - ClinVar

NM_004183.4(BEST1):c.889C>T (p.Pro297Ser)

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.

(8)

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.

Pathogenic/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_004183.4(BEST1):c.889C>T (p.Pro297Ser)

Variation ID: 99766 Accession: VCV000099766.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q12.3 11: 61959519 (GRCh38) [ NCBI UCSC ] 11: 61726991 (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	Feb 20, 2014	Oct 20, 2024	Jan 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004183.4:c.889C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004174.1:p.Pro297Ser	missense
NM_001139443.2:c.709C>T	NP_001132915.1:p.Pro237Ser	missense
NM_001300786.2:c.688-373C>T		intron variant
NM_001300787.2:c.709C>T	NP_001287716.1:p.Pro237Ser	missense
NM_001363591.2:c.571C>T	NP_001350520.1:p.Pro191Ser	missense
NM_001363592.1:c.1092C>T	NP_001350521.1:p.Thr364=	synonymous
NM_001363593.2:c.-84C>T		5 prime UTR
NR_134580.2:n.1205C>T		non-coding transcript variant
NC_000011.10:g.61959519C>T
NC_000011.9:g.61726991C>T
NG_009033.1:g.14636C>T
	O76090:p.Pro297Ser

... more HGVS ... less HGVS

Protein change

P297S, P237S, P191S

Other names

Canonical SPDI

NC_000011.10:61959518: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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA227836 UniProtKB: O76090#VAR_010485 dbSNP: rs1805143 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.
BEST1		-	-	GRCh38 GRCh37	831	903
FTH1		-	-	GRCh38 GRCh37	-	91

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	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 1, 2024	RCV000086184.30
Vitelliform macular dystrophy 2	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 15, 2022	RCV000678529.8

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 (Jan 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vitelliform macular dystrophy 2 Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761609.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Oct 17, 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: SCV002140936.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 13129869 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BEST1 protein function. ClinVar contains an entry for this variant (Variation ID: 99766). This missense change has been observed in individual(s) with autosomal dominant Best disease (PMID: 13129869). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs1805143, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 297 of the BEST1 protein (p.Pro297Ser). (less)
Pathogenic (Jan 01, 2024)	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: SCV001245805.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: BEST1: PM1, PM2, PM5, PP1:Moderate, PS4:Moderate, PP4 Number of individuals with the variant: 5
Pathogenic (Dec 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vitelliform macular dystrophy 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV002762864.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Clinical Features: Vitelliform-like macular lesions (present) , Macular dystrophy (present)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973519.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Likely pathogenic (Sep 01, 2016)	no assertion criteria provided Method: clinical testing	Vitelliform macular dystrophy 2 Affected status: yes Allele origin: inherited	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Accession: SCV000804602.2 First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018	Number of individuals with the variant: 1
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953179.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000118328.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_VMD2:c.891C>T

Comment:

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BEST1 protein function. ClinVar contains an entry for this variant (Variation ID: 99766). This missense change has been observed in individual(s) with autosomal dominant Best disease (PMID: 13129869). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs1805143, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 297 of the BEST1 protein (p.Pro297Ser).

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
Phenotype and genotype correlations in two best families.	Seddon JM	Ophthalmology	2003	PMID: 13129869

Text-mined citations for rs1805143 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_004183.4(BEST1):c.889C>T (p.Pro297Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1805143 ...