Submissions for variant NM_133459.4(CCBE1):c.902G>A (p.Arg301Gln)

gnomAD frequency: 0.00038  dbSNP: rs200772179

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001124794	SCV001283788	uncertain significance	Hennekam lymphangiectasia-lymphedema syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001350029	SCV001544401	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 301 of the CCBE1 protein (p.Arg301Gln). This variant is present in population databases (rs200772179, gnomAD 0.05%). This missense change has been observed in individual(s) with Hennekam lymphangiectasia-lymphedema syndrome (PMID: 28985353). ClinVar contains an entry for this variant (Variation ID: 890299). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CCBE1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002558231	SCV003593989	uncertain significance	Inborn genetic diseases	2021-05-17	criteria provided, single submitter	clinical testing	The c.902G>A (p.R301Q) alteration is located in exon 8 (coding exon 8) of the CCBE1 gene. This alteration results from a G to A substitution at nucleotide position 902, causing the arginine (R) at amino acid position 301 to be replaced by a glutamine (Q). The p.R301Q alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001124794	SCV003829317	uncertain significance	Hennekam lymphangiectasia-lymphedema syndrome 1	2021-09-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003396759	SCV004120682	uncertain significance	CCBE1-related disorder	2022-12-01	criteria provided, single submitter	clinical testing	The CCBE1 c.902G>A variant is predicted to result in the amino acid substitution p.Arg301Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-57106922-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV001124794	SCV005047157	uncertain significance	Hennekam lymphangiectasia-lymphedema syndrome 1	2024-05-08	criteria provided, single submitter	clinical testing	The CCBE1 c.902G>A (p.Arg301Gln) variant was identified at a near-heterozygous allelic fraction of 48%, a frequency which may be consistent with it being of germline origin. This variant has been reported in an individual affected with Hennekam lymphangiectasia–lymphedema syndrome (Brouillard P et al., PMID: 28985353) but was interpreted as a polymorphism due to the presence of two other likely causative variants in another gene. Computational predictors suggest that the variant does not impact CCBE1 function. This variant has been reported in the ClinVar database as a variant of uncertain significance by 5 submitters (ClinVar Variation ID: 890299). This variant is observed in 530/1,614,232 alleles in the general population (gnomAD v4.1.0). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.