ClinVar Miner

Submissions for variant NM_173689.7(CRB2):c.2400C>G (p.Asn800Lys) (rs765676223)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657852 SCV000779609 likely pathogenic not provided 2018-05-14 criteria provided, single submitter clinical testing The N800K variant in the CRB2 gene has been reported previously with another CRB2 variant in several individuals with features of CRB2-related disorder (Slavotinek et al., 2015; Lamont et al., 2016; Jaron et al., 2016). The N800K variant is observed in 50/9792 (0.5%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). In addition, the N800K variant has been identified in the homozygous state in one presumably healthy individual tested at GeneDx. The N800K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret N800K as a likely pathogenic variant.
Invitae RCV000657852 SCV001543250 uncertain significance not provided 2020-06-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 800 of the CRB2 protein (p.Asn800Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs765676223, ExAC 0.03%). This variant has been observed in combination with other CRB2 variants in individuals with clinical features of CRB2-related conditions (PMID: 25557780, 27004616,26925547). ClinVar contains an entry for this variant (Variation ID: 546072). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000157660 SCV000207611 pathogenic Ventriculomegaly with cystic kidney disease 2015-01-08 no assertion criteria provided literature only
Gharavi Laboratory,Columbia University RCV000657852 SCV000809309 pathogenic not provided 2018-09-16 no assertion criteria provided research
Reproductive Health Research and Development,BGI Genomics RCV000157660 SCV001142402 likely pathogenic Ventriculomegaly with cystic kidney disease 2020-01-06 no assertion criteria provided curation NM_173689.5:c.2400C>G in the CRB2 gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been detected in two siblings of a family affected with cerebral ventriculomegaly and renal microcysts, in trans with mutation c.2277G>A (p.Trp759Ter) and in another family in trans with mutation c.1928A>C (p.Glu643Ala) (PMID: 25557780). In-silico tools predict a damaging effect of the variant on protein function. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PP1; PP3.

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