Submissions for variant NM_004183.4(BEST1):c.56G>A (p.Arg19His)

gnomAD frequency: 0.00001  dbSNP: rs752923595

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002006249	SCV002269519	pathogenic	not provided	2024-05-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 19 of the BEST1 protein (p.Arg19His). This variant is present in population databases (rs752923595, gnomAD 0.006%). This missense change has been observed in individual(s) with nonsyndromic macular dystrophy (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1487156). 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%. This variant disrupts the p.Arg19 amino acid residue in BEST1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28687848). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004785435	SCV005398929	uncertain significance	Autosomal dominant vitreoretinochoroidopathy	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Dominant negative variants are associated with autosomal dominant disease (macular dystrophy, vitelliform, 2, MIM#153700; vitreoretinochoroidopathy, MIM#193220) while loss of function variants are associated with autosomal recessive disease (bestrophinopathy, autosomal recessive, MIM#611809; PMID: 29668979). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been observed in individuals with dominant vitelliform macular dystrophy (PMID: 21273940). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 4 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated bestrophin domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg19Leu) has been observed in an individual with vitelliform macular dystrophy, however the zygosity was unclear (PMID: 31254423). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been classified as likely pathogenic by a clinical laboratory in ClinVar, observed in heterozygous individuals with retinitis pigmentosa and another with bestrophinopathy, neither of whom had a second variant found (Invitae, internal communication). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816883	SCV005069742	uncertain significance	Retinal dystrophy	2022-01-01	no assertion criteria provided	clinical testing