ClinVar Miner

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

dbSNP: rs765676223
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657852 SCV000779609 pathogenic not provided 2021-11-16 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30212996, 27004616, 28425981, 25557780, 27867342, 26925547, 33969091, 30996265)
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.
Molecular Genetics, Royal Melbourne Hospital RCV000157660 SCV002498611 pathogenic Ventriculomegaly-cystic kidney disease 2022-04-05 criteria provided, single submitter clinical testing This sequence change is predicted to replace asparagine with lysine at codon 800 of the CRB2 protein, p.(Asn800Lys). The asparagine residue is highly conserved (100 vertebrates, UCSC), and is a glycosylation site N-linked (GlcNAc) asparagine in the laminin G-like 2 domain. There is a moderate physicochemical difference between asparagine and lysine. The variant is present in a large population cohort at a frequency of 0.02% (58/249,184 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.5% in the Ashkenazi Jewish sub-population. It has been identified with a second allele in at least five individuals with either or both ventriculomegaly (most common feature) and renal anomalies, and segregates with disease in multiple families (PMID: 25557780, 26925547, 27004616, 30996265). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PM2_Supporting, PP3.
OMIM RCV000157660 SCV000207611 pathogenic Ventriculomegaly-cystic kidney disease 2022-01-05 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-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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