rs1800995

Variant names:

• chr11-61955906-GC-AA
• rs1800995
• NM_004183.4:c.436_437delGCinsAA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Moderate PM1 PM2 PM5 PP5_Very_Strong

The NM_004183.4(BEST1):​c.436_437delGCinsAA​(p.Ala146Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A146S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BEST1 NM_004183.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 6.66

Genes affected

BEST1 (HGNC:12703): (bestrophin 1) This gene encodes a member of the bestrophin gene family. This small gene family is characterized by proteins with a highly conserved N-terminus with four to six transmembrane domains. Bestrophins may form chloride ion channels or may regulate voltage-gated L-type calcium-ion channels. Bestrophins are generally believed to form calcium-activated chloride-ion channels in epithelial cells but they have also been shown to be highly permeable to bicarbonate ion transport in retinal tissue. Mutations in this gene are responsible for juvenile-onset vitelliform macular dystrophy (VMD2), also known as Best macular dystrophy, in addition to adult-onset vitelliform macular dystrophy (AVMD) and other retinopathies. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Nov 2008]

LOC107984334 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_004183.4 (BEST1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a helix (size 5) in uniprot entity BEST1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_004183.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-61955906-G-T is described in Lovd as [Likely_pathogenic].
• PP5: Variant 11-61955906-GC-AA is Pathogenic according to our data. Variant chr11-61955906-GC-AA is described in ClinVar as [Pathogenic]. Clinvar id is 2736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEST1	NM_004183.4	c.436_437delGCinsAA	p.Ala146Lys	missense_variant		ENST00000378043.9	NP_004174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BEST1	ENST00000378043.9	c.436_437delGCinsAA	p.Ala146Lys	missense_variant		1	NM_004183.4	ENSP00000367282.4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Sep 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 146 of the BEST1 protein (p.Ala146Lys). This variant is present in population databases (rs1800995, gnomAD 0.0007%). This missense change has been observed in individuals with autosomal dominant Best disease (PMID: 10453731, 10737974, 11713080, 23139242). ClinVar contains an entry for this variant (Variation ID: 2736). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BEST1 function (PMID: 17898294, 23139242). For these reasons, this variant has been classified as Pathogenic. -

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Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 28, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.436_437delGCinsAA mutation in the BEST1 gene, which leads to substitution of Alanine 146 with a Lysine residue, has been reported previously in association with Best disease (Allikmets et al., 1999). We consider this variant to be pathogenic. -

Vitelliform macular dystrophy 2 Pathogenic:1

Jun 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800995; hg19: chr11-61723378;