VCV000004976.10 - ClinVar

NM_022436.3(ABCG5):c.1222C>T (p.Arg408Ter)

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.

(7)

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_022436.3(ABCG5):c.1222C>T (p.Arg408Ter)

Variation ID: 4976 Accession: VCV000004976.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 43824015 (GRCh38) [ NCBI UCSC ] 2: 44051154 (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 7, 2016	Nov 10, 2024	Aug 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_022436.3:c.1222C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071881.1:p.Arg408Ter	nonsense
NM_001348912.2:c.*16-3371G>A		intron variant
NM_001348913.2:c.*16-3371G>A		intron variant
NC_000002.12:g.43824015G>A
NC_000002.11:g.44051154G>A
NG_008883.1:g.19805C>T
NG_053008.1:g.54977G>A
LRG_1181:g.19805C>T
LRG_1181t1:c.1222C>T	LRG_1181p1:p.Arg408Ter

... more HGVS ... less HGVS

Protein change

R408*

Other names

Canonical SPDI

NC_000002.12:43824014: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

OMIM: 605459.0001 dbSNP: rs119479065 ClinGen: CA253370 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.
ABCG5		-	-	GRCh38 GRCh37	181	748
DYNC2LI1		-	-	GRCh38 GRCh37	168	693

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.
Sitosterolemia 2	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	-	RCV000005264.19
not provided	Pathogenic (2)	no assertion criteria provided	-	RCV001727512.12
Sitosterolemia	Pathogenic (1)	criteria provided, single submitter	Aug 20, 2023	RCV003505078.2

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.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sitosterolemia 2 Affected status: yes Allele origin: unknown	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002499585.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 Comment: Submitted to GoldVariant by Kathleen Freson, Center for Molecular and Vascular Biology, Leuven, Belgium	Publications: PubMed (1) PubMed: 34355501
Pathogenic (Aug 20, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Sitosterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004292453.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 11138003‚ 25665839‚ 11099417 Comment: This sequence change creates a premature translational stop signal (p.Arg408) in the ABCG5 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg408) in the ABCG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCG5 are known to be pathogenic (PMID: 11138003, 25665839). This variant is present in population databases (rs119479065, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ABCG5-related conditions (PMID: 11099417). ClinVar contains an entry for this variant (Variation ID: 4976). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sitosterolemia 2 Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002072959.1 First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022	Comment: The stop gained p.R408* in ABCG5 (NM_022436.3) has been reported previously in affected patients (Lee MH et al). It has been submitted to the Clinvar … (more) The stop gained p.R408* in ABCG5 (NM_022436.3) has been reported previously in affected patients (Lee MH et al). It has been submitted to the Clinvar database as Pathogenic. The p.R408* variant is observed in 3/30,616 (0.0098%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Reticulocytosis (present) , Abnormal erythrocyte morphology (present) , Giant platelets (present)
Pathogenic (Jan 01, 2001)	no assertion criteria provided Method: literature only	SITOSTEROLEMIA 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025442.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 22, 2019	Publications: PubMed (2) PubMed: 11099417‚ 11138003 Comment on evidence: In a Chinese patient with sitosterolemia (STSL2; 618666), Berge et al. (2000) identified a c.1222C-T transition in the ABCG5 gene, resulting in an arg408-to-ter (R408X) … (more) In a Chinese patient with sitosterolemia (STSL2; 618666), Berge et al. (2000) identified a c.1222C-T transition in the ABCG5 gene, resulting in an arg408-to-ter (R408X) substitution. No mutation was identified on the other allele; however, the patient had a cholesterol of 620 mg/dl. Lee et al. (2001) identified homozygosity for the R408X mutation in the ABCG5 gene in a Japanese patient (pedigree 3500) with sitosterolemia. (less)
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: SCV001976265.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Oct 31, 2024)	no assertion criteria provided Method: clinical testing	Sitosterolemia 2 Affected status: no Allele origin: germline	Department of Genetics, Suzhou Beikang Medical Laboratory Accession: SCV005387812.1 First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024	Comment: For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg408) in the ABCG5 gene. It … (more) For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg408) in the ABCG5 gene. It is expected to result in an absent or disrupted protein product. Loss of function is an established mechanism of disease for ABCG5 in autosomal recessive sitosterolaemia (PMID: 11138003, 25665839). ClinVar contains an entry for this variant (Variation ID: 4976). This variant is present in population databases (rs119479065, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Sitosterolemia 2 (PMID:11099417). (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001978768.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021

Comment:

This sequence change creates a premature translational stop signal (p.Arg408*) in the ABCG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCG5 are known to be pathogenic (PMID: 11138003, 25665839). This variant is present in population databases (rs119479065, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ABCG5-related conditions (PMID: 11099417). ClinVar contains an entry for this variant (Variation ID: 4976). For these reasons, this variant has been classified as Pathogenic.

Comment:

The stop gained p.R408* in ABCG5 (NM_022436.3) has been reported previously in affected patients (Lee MH et al). It has been submitted to the Clinvar database as Pathogenic. The p.R408* variant is observed in 3/30,616 (0.0098%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg408*) in the ABCG5 gene. It is expected to result in an absent or disrupted protein product. Loss of function is an established mechanism of disease for ABCG5 in autosomal recessive sitosterolaemia (PMID: 11138003, 25665839). ClinVar contains an entry for this variant (Variation ID: 4976). This variant is present in population databases (rs119479065, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Sitosterolemia 2 (PMID:11099417).

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
GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis.	Megy K	Journal of thrombosis and haemostasis : JTH	2021	PMID: 34355501
Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding.	Tada H	JIMD reports	2015	PMID: 25665839
Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.	Lee MH	Nature genetics	2001	PMID: 11138003
Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.	Berge KE	Science (New York, N.Y.)	2000	PMID: 11099417

Text-mined citations for rs119479065 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_022436.3(ABCG5):c.1222C>T (p.Arg408Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs119479065 ...