NM_004183.4(BEST1):c.851A>G (p.Tyr284Cys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 18, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000723944.21

Allele description [Variation Report for NM_004183.4(BEST1):c.851A>G (p.Tyr284Cys)]

NM_004183.4(BEST1):c.851A>G (p.Tyr284Cys)

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.851A>G (p.Tyr284Cys)

HGVS:

NC_000011.10:g.61958282A>G
NG_009033.1:g.13399A>G
NM_001139443.2:c.671A>G
NM_001300786.2:c.671A>G
NM_001300787.2:c.671A>G
NM_001363591.2:c.533A>G
NM_001363592.1:c.851A>G
NM_001363593.2:c.-325A>G
NM_004183.4:c.851A>GMANE SELECT
NP_001132915.1:p.Tyr224Cys
NP_001287715.1:p.Tyr224Cys
NP_001287716.1:p.Tyr224Cys
NP_001350520.1:p.Tyr178Cys
NP_001350521.1:p.Tyr284Cys
NP_004174.1:p.Tyr284Cys
NC_000011.9:g.61725754A>G
NM_001139443.1:c.671A>G
NM_004183.3:c.851A>G
NR_134580.2:n.964A>G

Protein change:

Y178C

Links:

dbSNP: rs727503824

NCBI 1000 Genomes Browser:

rs727503824

Molecular consequence:

NM_001363593.2:c.-325A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001139443.2:c.671A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001300786.2:c.671A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001300787.2:c.671A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363591.2:c.533A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363592.1:c.851A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004183.4:c.851A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_134580.2:n.964A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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
SCV000202249	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Apr 16, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000616654	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Sep 13, 2023)	germline	clinical testing	Citation Link,
SCV001206721	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21109774, 32207364, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000202249

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Uncertain significance
(Apr 16, 2014)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000616654

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Sep 13, 2023)

germline

clinical testing

Citation Link,

SCV001206721

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 18, 2024)

germline

clinical testing

PubMed (3)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Best's macular dystrophy in Australia: phenotypic profile and identification of novel BEST1 mutations.

Cohn AC, Turnbull C, Ruddle JB, Guymer RH, Kearns LS, Staffieri S, Daggett HT, Hewitt AW, Mackey DA.

Eye (Lond). 2011 Feb;25(2):208-17. doi: 10.1038/eye.2010.180. Epub 2010 Nov 26.

PubMed [citation]

PMID:: 21109774
PMCID:: PMC3169215

"Novel p.Tyr284Cys BEST1 genotype-phenotype correlations of Vitelliform Macular Dystrophy in a family with incomplete penetrance".

Garza-Garza LA, León-Cachón RBR, Aguirre-Garza M, Garza-Leon M.

Ophthalmic Genet. 2020 Apr;41(2):183-188. doi: 10.1080/13816810.2020.1744020. Epub 2020 Mar 24.

PubMed [citation]

PMID:: 32207364

See all PubMed Citations (3)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000202249.7

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

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000616654.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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; This variant is associated with the following publications: (PMID: 35754583, 33090715, 21109774, 35973442, 32207364)

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

From Invitae, SCV001206721.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 284 of the BEST1 protein (p.Tyr284Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant BEST1-related conditions (PMID: 21109774, 32207364; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 166746). 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 with a positive predictive value of 95%. 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: Apr 15, 2024

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