Submissions for variant NM_172351.3(CD46):c.643G>A (p.Val215Met)

gnomAD frequency: 0.00003  dbSNP: rs535353049

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001355611	SCV003523377	uncertain significance	not provided	2022-06-27	criteria provided, single submitter	clinical testing	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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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. ClinVar contains an entry for this variant (Variation ID: 1049467). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the CD46 protein (p.Val215Met). This variant is present in population databases (rs535353049, gnomAD 0.02%). This missense change has been observed in individual(s) with primary glomerulonephritis (PMID: 17018561).
Neuberg Centre For Genomic Medicine, NCGM	RCV003339613	SCV004048460	uncertain significance	Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly		criteria provided, single submitter	clinical testing	The missense variant in c.643G>A (p.Val215Met) in CD46 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This Variant has an allele frequency of 0.003181% in gnomAD database. In silico tools predict the variant to be tolerated. The amino acid Val at position 215 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355611	SCV001550544	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CD46 p.Val215Met variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs535353049) and in control databases in 8 of 251466 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 7 of 30614 chromosomes (freq: 0.000229) and European (non-Finnish) in 1 of 113748 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The p.Val215 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.