Converted during submission to Likely benign.
ClinVar Genomic variation as it relates to human health
NM_016579.4(CD320):c.256GAG[2] (p.Glu88del)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2); Benign(3); Likely benign(1)
Likely pathogenic(1); Uncertain significance(2); Benign(3); Likely benign(1)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_016579.4(CD320):c.256GAG[2] (p.Glu88del)
Variation ID: 203643 Accession: VCV000203643.23
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 19p13.2 19: 8305035-8305037 (GRCh38) [ NCBI UCSC ] 19: 8369919-8369921 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 8, 2016 Nov 24, 2024 Aug 26, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_016579.4:c.256GAG[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057663.1:p.Glu88del inframe deletion NM_016579.4:c.262_264del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001165895.2:c.143-955GAG[2] intron variant NM_016579.3:c.262_264del NC_000019.10:g.8305035CTC[2] NC_000019.9:g.8369919CTC[2] NG_028124.1:g.8314GAG[2] - Protein change
- E88del
- Other names
- -
- Canonical SPDI
- NC_000019.10:8305034:CTCCTCCTC:CTCCTC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00699 (CTCCTC)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| CD320 | - | - |
GRCh38 GRCh37 |
169 | 179 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 26, 2024 | RCV000004499.25 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Aug 26, 2024 | RCV000224888.22 | |
|
CD320-related disorder
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Likely pathogenic (1) |
no assertion criteria provided
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Jun 12, 2024 | RCV003398922.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Mar 18, 2016)
|
criteria provided, single submitter
Method: reference population
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Methylmalonic acidemia due to transcobalamin receptor defect
Affected status: unknown
Allele origin:
germline
|
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267241.1
First in ClinVar: Jan 23, 2017 Last updated: Jan 23, 2017 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
|
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Likely Benign
(Feb 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280766.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Converted during submission to Likely benign.
|
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Benign
(May 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000238758.13
First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 20524213, 29040465, 29663633, 30041674, 22819238, 31180159, 31462756)
|
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Benign
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Methylmalonic acidemia due to transcobalamin receptor defect
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV001140969.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
|
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Uncertain significance
(Jan 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic acidemia due to transcobalamin receptor defect
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000676997.9
First in ClinVar: Jan 23, 2017 Last updated: Feb 20, 2024 |
Comment:
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. … (more)
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. (less)
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Benign
(Aug 01, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV005329663.2
First in ClinVar: Oct 08, 2024 Last updated: Oct 20, 2024 |
Comment:
CD320: PM4:Supporting, BS1, BS2
Number of individuals with the variant: 1
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Uncertain significance
(Aug 26, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005408704.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PM4
Number of individuals with the variant: 1
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Pathogenic
(Aug 01, 2010)
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no assertion criteria provided
Method: literature only
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METHYLMALONIC ACIDURIA, TRANSIENT, DUE TO TRANSCOBALAMIN RECEPTOR DEFECT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024673.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 23, 2017 |
Comment on evidence:
In an infant with methylmalonic aciduria (613646) detected by newborn screening, Quadros et al. (2010) identified a homozygous 3-bp deletion (262delGAG) in the CD320 gene, … (more)
In an infant with methylmalonic aciduria (613646) detected by newborn screening, Quadros et al. (2010) identified a homozygous 3-bp deletion (262delGAG) in the CD320 gene, resulting in an in-frame deletion of glu88 in the 3-prime end of the first LDLR type A domain. Newborn screening identified increased blood C3-acylcarnitine levels, and urinary analysis showed moderately elevated MMA. Plasma vitamin B12 and total homocysteine levels were normal. Repeat screening on day 14 of life showed normal C3-acylcarnitine levels and increased MMA; vitamin B12 was administered intramuscularly, and MMA returned to normal. All hematologic parameters were normal, and the mother had no laboratory abnormalities. Studies of patient fibroblasts showed increased levels of MMA and homocysteine compared to control cells, but these levels decreased in the presence of high levels of cobalamin. Patient fibroblasts showed low uptake of transcobalamin-bound cobalamin, but normal conversion to adenosylcobalamin and methylcobalamin, suggesting a defect in the receptor. Insertion of the missing codon by site-directed mutagenesis fully restored TCBLR function. Studies of 4 additional cell lines derived from patients with similar features identified the same mutation; 2 of these additional patients had increased serum homocysteine. Karth et al. (2012) described a 7-week-old male who presented with bilateral central retinal artery occlusions (CRAO) following incision and drainage of an inguinal lymph node abscess 2 days before and short course of clindamycin preoperatively. Laboratory studies showed elevated serum homocysteine and MMA, indicating a functional deficit of vitamin B12 although serum levels of B12 were normal. DNA analysis of patient fibroblasts revealed homozygosity for an in-frame deletion of glu88 (262_264delGAG) of the CD320 gene. After 5 days of treatment with intravenous vitamin B6 and intramuscular B12-hydroxocobalamine, serum homocysteine was nearly normalized and serum MMA was normalized. At follow-up at 4 months of age, the patient's vitamin B12, homocysteine, and MMA levels were within normal limits. Karth et al. (2012) noted that hyperhomocysteinemia is a known risk factor for retinal vascular occlusive disease; the CRAO in this patient resulted in severe vision loss. (less)
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Likely pathogenic
(Jun 12, 2024)
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no assertion criteria provided
Method: clinical testing
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CD320-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004105179.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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other
Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
(Mar 15, 2017)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000700738.2
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Number of individuals with the variant: 1
Sex: mixed
|
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This variant is associated with the following publications: (PMID: 20524213, 29040465, 29663633, 30041674, 22819238, 31180159, 31462756)
Comment:
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.
Comment:
CD320: PM4:Supporting, BS1, BS2
Comment:
PM4
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Converted during submission to Likely benign.
Comment:
This variant is associated with the following publications: (PMID: 20524213, 29040465, 29663633, 30041674, 22819238, 31180159, 31462756)
Comment:
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.
Comment:
CD320: PM4:Supporting, BS1, BS2
Comment:
PM4
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Vitamin B(12) Metabolism: A Network of Multi-Protein Mediated Processes. | Mucha P | International journal of molecular sciences | 2024 | PMID: 39125597 |
| Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene. | Pangilinan F | American journal of medical genetics. Part A | 2022 | PMID: 35107211 |
| CD320 expression and apical membrane targeting in renal and intestinal epithelial cells. | Chen Y | International journal of biological macromolecules | 2022 | PMID: 34998874 |
| Transcobalamin receptor deficiency in seven asymptomatic patients ascertained through newborn screening. | Pappas KB | American journal of medical genetics. Part A | 2022 | PMID: 34978764 |
| The role of exome sequencing in newborn screening for inborn errors of metabolism. | Adhikari AN | Nature medicine | 2020 | PMID: 32778825 |
| Genome and RNA sequencing in patients with methylmalonic aciduria of unknown cause. | Abdrabo LS | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31462756 |
| A Vietnamese human genetic variation database. | Le VS | Human mutation | 2019 | PMID: 31180159 |
| Transcobalamin receptor defect: Identification of two new cases through positive newborn screening for propionic/methylmalonic aciduria and long-term outcome. | Hannah-Shmouni F | American journal of medical genetics. Part A | 2018 | PMID: 29663633 |
| Analysis of protein-coding genetic variation in 60,706 humans. | Lek M | Nature | 2016 | PMID: 27535533 |
| Structural basis of transcobalamin recognition by human CD320 receptor. | Alam A | Nature communications | 2016 | PMID: 27411955 |
| Bilateral central retinal artery occlusions in an infant with hyperhomocysteinemia. | Karth P | Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus | 2012 | PMID: 22819238 |
| Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). | Quadros EV | Human mutation | 2010 | PMID: 20524213 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CD320 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs150384171 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.