VCV000581662.21 - ClinVar

NM_001081.4(CUBN):c.5428C>T (p.Arg1810Ter)

Germline

Classification

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)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001081.4(CUBN):c.5428C>T (p.Arg1810Ter)

Variation ID: 581662 Accession: VCV000581662.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10p13 10: 16940152 (GRCh38) [ NCBI UCSC ] 10: 16982151 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 10, 2018	Oct 8, 2024	May 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001081.4:c.5428C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001072.2:p.Arg1810Ter	nonsense
NC_000010.11:g.16940152G>A
NC_000010.10:g.16982151G>A
NG_008967.1:g.194666C>T
LRG_540:g.194666C>T
LRG_540t1:c.5428C>T	LRG_540p1:p.Arg1810Ter

... more HGVS ... less HGVS

Protein change

R1810*

Other names

Canonical SPDI

NC_000010.11:16940151:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00013

Trans-Omics for Precision Medicine (TOPMed) 0.00013

The Genome Aggregation Database (gnomAD) 0.00019

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Links

dbSNP: rs143944436 VarSome

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
Gene	OMIM	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.
CUBN		-	-	GRCh38 GRCh37	1777	1846

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.
Imerslund-Grasbeck syndrome	Pathogenic (3)	criteria provided, single submitter	Oct 5, 2023	RCV000705555.8
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 30, 2024	RCV001547777.11
Imerslund-Grasbeck syndrome type 1 Proteinuria, chronic benign	Pathogenic (1)	criteria provided, single submitter	May 31, 2022	RCV001536070.3
Autism spectrum disorder	Likely pathogenic (1)	no assertion criteria provided	Jul 28, 2023	RCV003313972.3
CUBN-related disorder	Pathogenic (1)	no assertion criteria provided	Nov 29, 2023	RCV003918139.2

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.
Pathogenic (May 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Imerslund-Grasbeck syndrome type 1 Proteinuria, chronic benign Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV001752767.2 First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022
Pathogenic (Jun 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019781.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Imerslund-Grasbeck syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000834556.3 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 28492532‚ 15024727‚ 22929189‚ 25349199‚ 31613795‚ 34979989 Comment: This sequence change creates a premature translational stop signal (p.Arg1810) in the CUBN gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg1810) in the CUBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CUBN are known to be pathogenic (PMID: 15024727, 22929189, 25349199, 31613795, 34979989). This variant is present in population databases (rs143944436, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of Imerslund-Gr√§sbeck syndrome (PMID: 31613795). ClinVar contains an entry for this variant (Variation ID: 581662). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (May 30, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001767560.5 First in ClinVar: Aug 07, 2021 Last updated: Oct 08, 2024	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25635822, 31589614, 35064937, 31613795) (less)
Likely pathogenic (Jun 07, 2017)	no assertion criteria provided Method: curation	Imerslund-Grasbeck syndrome type 1 Affected status: no Allele origin: germline	SingHealth Duke-NUS Institute of Precision Medicine Accession: SCV000853127.1 First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018
Likely pathogenic (May 09, 2018)	no assertion criteria provided Method: clinical testing	Imerslund-Grasbeck syndrome type 1 Affected status: yes Allele origin: germline	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare Accession: SCV000863860.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002037528.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002037905.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021
Likely pathogenic (Jul 28, 2023)	no assertion criteria provided Method: clinical testing	Autism spectrum disorder Affected status: yes Allele origin: unknown	Gene Friend Way, National Innovation Center Accession: SCV004013903.2 First in ClinVar: Jul 22, 2023 Last updated: Aug 30, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease. In … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease. In our study, two children diagnosed with severe Autism Spectrum Disorder (ASD) are carriers of this mutation, among the two patients, one also carries another variant known to associate with ASD (SRD5A2 (rs9332964)). (less) Number of individuals with the variant: 2 Method: 800K direct targets snp array, validated with Sanger sequencing
Pathogenic (Nov 29, 2023)	no assertion criteria provided Method: clinical testing	CUBN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004727822.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The CUBN c.5428C>T variant is predicted to result in premature protein termination (p.Arg1810). This variant was reported with a second CUBN variant in two patients … (more) The CUBN c.5428C>T variant is predicted to result in premature protein termination (p.Arg1810). This variant was reported with a second CUBN variant in two patients with kidney disease; however, phase of the variants was not determined (Supp. Table 2 in Bedin et al. 2020. PubMed ID: 31613795). Of note, the c.5428C>T has been reported with the c.6088C>T (p.Arg2030*) variant in two patients in the literature, but segregation analysis was not completed to determine phase (Family 21, Supp Table 2 in Bedin et al. 2020. PubMed ID: 31613795; Case #20, Supp. Table 3 in Lu L et al 2022. PubMed ID: 35064937). At PreventionGenetics, we have observed the c.6088C>T and c.5428C>T variants to occur on the same allele (cis phase) based on parental follow up testing (internal data). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. Nonsense variants in CUBN are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Arg1810*) in the CUBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CUBN are known to be pathogenic (PMID: 15024727, 22929189, 25349199, 31613795, 34979989). This variant is present in population databases (rs143944436, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of Imerslund-Gr√§sbeck syndrome (PMID: 31613795). ClinVar contains an entry for this variant (Variation ID: 581662). For these reasons, this variant has been classified as Pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25635822, 31589614, 35064937, 31613795)

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease. In our study, two children diagnosed with severe Autism Spectrum Disorder (ASD) are carriers of this mutation, among the two patients, one also carries another variant known to associate with ASD (SRD5A2 (rs9332964)).

Comment:

The CUBN c.5428C>T variant is predicted to result in premature protein termination (p.Arg1810*). This variant was reported with a second CUBN variant in two patients with kidney disease; however, phase of the variants was not determined (Supp. Table 2 in Bedin et al. 2020. PubMed ID: 31613795). Of note, the c.5428C>T has been reported with the c.6088C>T (p.Arg2030*) variant in two patients in the literature, but segregation analysis was not completed to determine phase (Family 21, Supp Table 2 in Bedin et al. 2020. PubMed ID: 31613795; Case #20, Supp. Table 3 in Lu L et al 2022. PubMed ID: 35064937). At PreventionGenetics, we have observed the c.6088C>T and c.5428C>T variants to occur on the same allele (cis phase) based on parental follow up testing (internal data). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. Nonsense variants in CUBN are expected to be pathogenic. This variant is interpreted as pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
CUBN gene mutations may cause focal segmental glomerulosclerosis (FSGS) in children.	Yang J	BMC nephrology	2022	PMID: 34979989
Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.	Bedin M	The Journal of clinical investigation	2020	PMID: 31613795
A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.	Sadowski CE	Journal of the American Society of Nephrology : JASN	2015	PMID: 25349199
Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns.	Tanner SM	Orphanet journal of rare diseases	2012	PMID: 22929189
Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East.	Tanner SM	Human mutation	2004	PMID: 15024727

Text-mined citations for rs143944436 ...

These 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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_001081.4(CUBN):c.5428C>T (p.Arg1810Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs143944436 ...