Submissions for variant NM_016579.4(CD320):c.256GAG[2] (p.Glu88del)

dbSNP: rs150384171

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000224888	SCV000238758	benign	not provided	2018-05-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20524213, 29040465, 29663633, 30041674, 22819238, 31180159, 31462756)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000004499	SCV000267241	likely pathogenic	Methylmalonic acidemia due to transcobalamin receptor defect	2016-03-18	criteria provided, single submitter	reference population
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224888	SCV000280766	likely benign	not provided	2016-02-02	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004499	SCV000676997	uncertain significance	Methylmalonic acidemia due to transcobalamin receptor defect	2024-01-26	criteria provided, single submitter	clinical testing	This variant, c.262_264del, results in the deletion of 1 amino acid(s) of the CD320 protein (p.Glu88del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs150384171, gnomAD 1.4%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with methylmalonic aciduria (PMID: 20524213, 22819238, 29663633, 34978764; Invitae). ClinVar contains an entry for this variant (Variation ID: 203643). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CD320 function (PMID: 20524213, 27411955). 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.
Mendelics	RCV000004499	SCV001140969	benign	Methylmalonic acidemia due to transcobalamin receptor defect	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224888	SCV005329663	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	CD320: PM4:Supporting, BS1, BS2
Mayo Clinic Laboratories, Mayo Clinic	RCV000224888	SCV005408704	uncertain significance	not provided	2024-08-26	criteria provided, single submitter	clinical testing	PM4
OMIM	RCV000004499	SCV000024673	pathogenic	Methylmalonic acidemia due to transcobalamin receptor defect	2010-08-01	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000224888	SCV000700738	other	not provided	2017-03-15	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398922	SCV004105179	likely pathogenic	CD320-related disorder	2024-06-12	no assertion criteria provided	clinical testing	The CD320 c.262_264delGAG variant is predicted to result in an in-frame deletion (p.Glu88del). This variant has been reported in the homozygous or compound heterozygous state in patients with methylmalonic acidemia and homocysteinemia due to transcobalamin receptor deficiency (e.g., Quadros et al. 2010. PubMed ID: 20524213; Karth et al. 2012. PubMed ID: 22819238; Hannah-Shmouni et al. 2018. PubMed ID: 29663633; Pappas et al. 2022. PubMed ID: 34978764). Fibroblast cells from patients apparently homozygous for the CD320 c.262_264del (p.Glu88del) variant showed reduced uptake of holo-transcobalamin (holo-TC) as well as elevated levels of homocysteine and methylmalonic acid in culture medium (Quadros et al. 2010. PubMed ID: 20524213; Pangilinan et al. 2022. PubMed ID: 35107211). The c.262_264del variant has been reported in a large population database at an allele frequency of up to ~1.4%, which would be high for an autosomal recessive disorder with a severe phenotype. It should be noted, however, that most reported patients with transcobalamin receptor deficiency have been clinically asymptomatic. These data suggest that this may possibly be a benign biochemical phenotype, although the long-term outcome in these individuals is not currently well understood (Hannah-Shmouni et al. 2018. PubMed ID: 29663633). In summary, we classify the c.262_264del (p.Glu88del) variant as likely pathogenic for recessive transcobalamin receptor deficiency.