Submissions for variant NM_000496.3(CRYBB2):c.463C>T (p.Gln155Ter)

dbSNP: rs74315489

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760465	SCV000890353	pathogenic	not provided	2022-12-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced protein-protein interaction (Liu et al., 2005); Nonsense variant predicted to result in protein truncation, as the last 51 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11424921, 16179907, 28839118, 21245961, 9158139, 8812489, 17234267, 2240043, 10634616, 15889016, 24319337, 18449377, 28025620, 22846113, 19321936, 29395391, 27385965, 29652984, 30078984)
3billion	RCV000018458	SCV002521696	pathogenic	Cataract 3 multiple types	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 15889016). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11424921, 17234267). The variant has been reported to be associated with CRYBB2 related disorder (ClinVar ID: VCV000016949 / PMID: 9158139). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV000018458	SCV003444373	pathogenic	Cataract 3 multiple types	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln155*) in the CRYBB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the CRYBB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant congenital cataract (PMID: 9158139, 27385965, 29395391). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16949). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398538	SCV004104786	pathogenic	CRYBB2-related condition	2023-11-27	criteria provided, single submitter	clinical testing	The CRYBB2 c.463C>T variant is predicted to result in premature protein termination (p.Gln155*). This variant segregated with autosomal dominant cerulean cataract in multiple families (Litt et al. 1997. PubMed ID: 9158139; Messina-Baas et al. 2016. PubMed ID: 27385965; Javadiyan et al. 2017. PubMed ID: 28839118; Ching et al. 2018. PubMed ID: 29395391; Zhang et al. 2018. PubMed ID: 30078984). In addition, there is evidence in the literature supporting that this variant likely arose from a gene conversion event between the CRYBB2 gene and its pseudogene, CRYBB2P1 (Vanita et al. 2001. PubMed ID: 11424921; Bateman et al. 2007. PubMed ID: 17234267). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in CRYBB2 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000018458	SCV000038740	pathogenic	Cataract 3 multiple types	2007-03-01	no assertion criteria provided	literature only
Department of Ophthalmology, Flinders University	RCV000490780	SCV000297756	likely pathogenic	Developmental cataract	2016-07-29	no assertion criteria provided	clinical testing