Submissions for variant NM_004183.4(BEST1):c.1415del (p.Leu472fs)

gnomAD frequency: 0.00006  dbSNP: rs752125512

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779068	SCV000915535	likely pathogenic	Vitelliform macular dystrophy 2	2018-10-18	criteria provided, single submitter	clinical testing	The BEST1 c.1415delT (p.Leu472ProfsTer10) variant results in a frameshift that is predicted to result in a premature termination of the protein. The p.Leu472ProfsTer10 variant has been reported in one study in which it was identified in a homozygous state in two siblings with autosomal recessive Best disease (Bitner et al. 2011). Segregation analysis revealed that both parents, two grandmothers, and three uncles were heterozygous for the variant but were unaffected, consistent with autosomal recessive inheritance. The index case was also homozygous for four silent variants previously described as non-pathogenic. Both carrier parents were heterozygous for the same four silent variants, which were shown to be in cis with the p.Leu472ProfsTer10 variant. The p.Leu472ProfsTer10 variant was reported in a heterozygous state in one of 112 ethnically matched controls (Bitner et al. 2011) and is reported at a frequency of 0.001320 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies conducted in MDCK cell monolayers indicated the variant has no effect on protein localization or oligomerization compared with the wild type protein (Johnson et al. 2014). However, based on their analysis of 28 BEST1 mutants, Johnson et al. conclude that Best vitelliform macular dystrophy is not associated with oligomeric defects and that mislocalization is not sufficient to produce disease. Based on the evidence, the p.Leu472ProfsTer10 variant is classified as likely pathogenic for Best vitelliform macular dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001380021	SCV001577947	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu472Profs*10) in the BEST1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BEST1 are known to be pathogenic (PMID: 21825197). This variant is present in population databases (rs752125512, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Best vitelliform macular dystrophy (PMID: 21467170). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 632163). For these reasons, this variant has been classified as Pathogenic.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000779068	SCV001160931	pathogenic	Vitelliform macular dystrophy 2	2019-06-23	no assertion criteria provided	research