Submissions for variant NM_001081.4(CUBN):c.8894T>C (p.Phe2965Ser)

gnomAD frequency: 0.00133  dbSNP: rs117620008

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000766837	SCV000603274	uncertain significance	not provided	2022-10-19	criteria provided, single submitter	clinical testing	The CUBN c.8894T>C; p.Phe2965Ser variant (rs117620008), to our knowledge, is not reported in the medical literature associated with disease, but is reported in ClinVar (Variation ID: 439582). This variant is found in the non-Finnish European population with an allele frequency of 0.27% (387/282680 alleles) in the Genome Aggregation Database. The phenylalanine at codon 2965 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.404). Due to limited information, the clinical significance of this variant is uncertain at this time.
GeneDx	RCV000766837	SCV000616693	uncertain significance	not provided	2017-07-31	criteria provided, single submitter	clinical testing	The F2965S variant in the CUBN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The F2965S variant is observed in 167/66388 (0.25%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The F2965S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret F2965S as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001029961	SCV001001737	likely benign	Imerslund-Grasbeck syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001106016	SCV001263040	uncertain significance	Imerslund-Grasbeck syndrome type 1	2018-01-12	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.
PreventionGenetics, part of Exact Sciences	RCV003403188	SCV004103486	uncertain significance	CUBN-related disorder	2022-09-12	criteria provided, single submitter	clinical testing	The CUBN c.8894T>C variant is predicted to result in the amino acid substitution p.Phe2965Ser. This variant has been reported as “variant likely pathogenic” in a large study of whole-exome sequencing, but the clinical significance was not established with sufficient evidence (Supplemental Table 3 at Retterer et al. 2016. PubMed ID: 26633542). This variant is reported in 0.27% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-16930427-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000766837	SCV004126489	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing	CUBN: PM2, PP3
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV001029961	SCV001192759	uncertain significance	Imerslund-Grasbeck syndrome	2019-07-25	no assertion criteria provided	clinical testing