rs1800995

Positions:

• chr11-61955906-GC-AA

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_437delinsAA​(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 same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A146S) has been classified as Uncertain significance.

• 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 hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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/exons	MANE	UniProt
BEST1	NM_004183.4	c.436_437delinsAA	p.Ala146Lys	missense_variant	4/11	ENST00000378043.9
LOC107984334	XR_001748245.2	n.2787_2788delinsTT		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEST1	ENST00000378043.9	c.436_437delinsAA	p.Ala146Lys	missense_variant	4/11	1	NM_004183.4	P1

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 16, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BEST1 function (PMID: 17898294, 23139242). 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. ClinVar contains an entry for this variant (Variation ID: 2736). This missense change has been observed in individuals with autosomal dominant Best disease (PMID: 10453731, 10737974, 11713080, 23139242). This variant is present in population databases (rs1800995, gnomAD 0.0007%). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2015	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. -
not provided, no classification provided	literature only	Retina International	-	- -

Vitelliform macular dystrophy 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1999

- -

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;