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

Clinical significance:Uncertain significance (Last evaluated: Aug 14, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000723944.4

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
  • 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:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000202249EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Apr 16, 2014)
germlineclinical testing

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

Citation Link,

SCV000616654GeneDxcriteria provided, single submitter
Uncertain significance
(Jun 23, 2017)
germlineclinical testing

Citation Link,

SCV001206721Invitaecriteria provided, single submitter
Uncertain significance
(Aug 14, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown1not providednot providednot providednot providedclinical 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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000202249.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From GeneDx, SCV000616654.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The Y284C variant in the BEST1 gene has been reported previously in an individual with Best macular dystrophy (Cohn et al., 2011). This variant has also been observed in other individuals undergoing BEST1 testing at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y284C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Y284C as a variant of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001206721.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces tyrosine with cysteine at codon 284 of the BEST1 protein (p.Tyr284Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant vitelliform macular dystrophy (PMID: 21109774). ClinVar contains an entry for this variant (Variation ID: 166746). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 16, 2021

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