Submissions for variant NM_019098.5(CNGB3):c.1405T>G (p.Tyr469Asp)

gnomAD frequency: 0.00248  dbSNP: rs35365413

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000378015	SCV000339697	likely benign	not specified	2016-02-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000497748	SCV000800595	uncertain significance	Achromatopsia 3	2017-09-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000881356	SCV001024524	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000378015	SCV004240865	likely benign	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: CNGB3 c.1405T>G (p.Tyr469Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 251070 control chromosomes, predominantly at a frequency of 0.0082 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGB3 causing Achromatopsia phenotype (0.005), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1405T>G has been reported in the literature in settings of limited gene panel testing in heterozygous individuals with no reported second variant affected with achromatopsia (e.g. Mayer_2017, Weisschuh_2020), in at least one compound heterozygous individual affected with macular degeneration (e.g. Sun_2020, Nishiguchi_2005), or by WES in a heterozygous individual affected with severe Retinitis Pigmentosa (e.g. Ganapathi_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Achromatopsia. One publication reports experimental evidence evaluating an impact on protein function, suggesting the variant may enhance the intrinsic (ligand independent) gating properties of CNG channels in vitro, however, additional evidence is necessary to allow convincing conclusions about the variant effect in disease (e.g. Meighan_2015). The following publications have been ascertained in the context of this evaluation (PMID: 35672425, 28795510, 26106334, 15712225, 32913385, 31544997). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=2), likely benign (n=1), uncertain significance (n=1), or likely pathogenic (n=1). Based on the conflicting evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000881356	SCV004701056	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CNGB3: BS2
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000378015	SCV004847437	likely benign	not specified	2024-02-05	criteria provided, single submitter	clinical testing	The p.Tyr469Asp variant in CNGB3 is classified as likely benign because it has been identified in 0.8% (347/41448) of African chromosomes, including 1 homozygote by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1.
OMIM	RCV000005538	SCV000025720	uncertain significance	Severe early-childhood-onset retinal dystrophy	2005-03-01	no assertion criteria provided	literature only
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV000497748	SCV000575813	likely pathogenic	Achromatopsia 3	2017-03-27	no assertion criteria provided	research
Natera, Inc.	RCV001276134	SCV001461985	benign	Achromatopsia	2020-01-08	no assertion criteria provided	clinical testing