Submissions for variant NM_004076.5(CRYBB3):c.547G>T (p.Glu183Ter)

gnomAD frequency: 0.00135  dbSNP: rs147328317

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553645	SCV000642008	benign	Cataract 22 multiple types	2022-10-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000553645	SCV001307046	uncertain significance	Cataract 22 multiple types	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
PreventionGenetics, part of Exact Sciences	RCV003431088	SCV004118324	uncertain significance	CRYBB3-related disorder	2023-09-21	criteria provided, single submitter	clinical testing	The CRYBB3 c.547G>T variant is predicted to result in premature protein termination (p.Glu183*). This variant occurs within the terminal exon of CRYBB3 and is predicted to shorten the coding sequence by 28 amino acids. This variant was reported in a family with congenital cataracts; however, all affected family members harbored a pathogenic variant in EPHA2. The CRYBB3 (p.Glu183*) did not segregate with the disorder and was excluded from further analysis (Reis et al. 2014. PubMed ID: 24940039). This variant was also reported in the heterozygous state in an individual with early-onset high myopia (eoHM); however, this patient also had additional variants in other candidate genes and all variants were reported to be maternally-inherited (Patient OFT-00332 in González-Iglesias et al 2022. PubMed ID: 35457050). This variant is reported in 1.9% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including two homozygous individuals (http://gnomad.broadinstitute.org/variant/22-25603090-G-T). Loss of function has not been a well documented cause of CRYBB3-related disease (Human Gene Mutation Database). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV003431087	SCV004154757	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	CRYBB3: BS2