NM_004183.4(BEST1):c.240C>G (p.Phe80Leu) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 30, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001959058.6

Allele description [Variation Report for NM_004183.4(BEST1):c.240C>G (p.Phe80Leu)]

NM_004183.4(BEST1):c.240C>G (p.Phe80Leu)

Gene:

BEST1:bestrophin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q12.3

Genomic location:

Preferred name:

NM_004183.4(BEST1):c.240C>G (p.Phe80Leu)

HGVS:

NC_000011.10:g.61955194C>G
NG_009033.1:g.10311C>G
NM_001139443.2:c.60C>G
NM_001300786.2:c.60C>G
NM_001300787.2:c.60C>G
NM_001363592.1:c.240C>G
NM_004183.4:c.240C>GMANE SELECT
NP_001132915.1:p.Phe20Leu
NP_001287715.1:p.Phe20Leu
NP_001287716.1:p.Phe20Leu
NP_001350521.1:p.Phe80Leu
NP_004174.1:p.Phe80Leu
NC_000011.9:g.61722666C>G
NR_134580.2:n.353C>G

Protein change:

F20L

Links:

dbSNP: rs281865221

NCBI 1000 Genomes Browser:

rs281865221

Molecular consequence:

NM_001139443.2:c.60C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001300786.2:c.60C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001300787.2:c.60C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363592.1:c.240C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004183.4:c.240C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_134580.2:n.353C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002246570	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 30, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21878505, 25082885, 26201355, 28806213, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002246570

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 30, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Disease-associated missense mutations in bestrophin-1 affect cellular trafficking and anion conductance.

Milenkovic VM, Röhrl E, Weber BH, Strauss O.

J Cell Sci. 2011 Sep 1;124(Pt 17):2988-96. doi: 10.1242/jcs.085878.

PubMed [citation]

PMID:: 21878505

Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss.

Alapati A, Goetz K, Suk J, Navani M, Al-Tarouti A, Jayasundera T, Tumminia SJ, Lee P, Ayyagari R.

Invest Ophthalmol Vis Sci. 2014 Jul 31;55(9):5510-21. doi: 10.1167/iovs.14-14359.

PubMed [citation]

PMID:: 25082885
PMCID:: PMC4152151

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002246570.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 80 of the BEST1 protein (p.Phe80Leu). This variant is not present in population databases (gnomAD no frequency). A different variant (c.240C>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 21878505, 25082885, 26201355). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 1459557). 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. This variant disrupts the p.Phe80 amino acid residue in BEST1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21878505, 25082885, 26201355, 28806213). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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