ClinVar Genomic variation as it relates to human health
NM_003661.4(APOL1):c.1164_1169del (p.Asn388_Tyr389del)
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.
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.
Likely risk allele(1); Uncertain significance(1); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003661.4(APOL1):c.1164_1169del (p.Asn388_Tyr389del)
Variation ID: 6081 Accession: VCV000006081.20
- Type and length
-
Deletion, 6 bp
- Location
-
Cytogenetic: 22q12.3 22: 36265996-36266001 (GRCh38) [ NCBI UCSC ] 22: 36662042-36662047 (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 Apr 4, 2013 Feb 20, 2024 Jan 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003661.4:c.1164_1169del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003652.2:p.Asn388_Tyr389del inframe deletion NM_001136540.2:c.1164_1169del NP_001130012.1:p.Asn388_Tyr389del inframe deletion NM_001136541.2:c.1110_1115del NP_001130013.1:p.Asn370_Tyr371del inframe deletion NM_001362927.2:c.1110_1115del NP_001349856.1:p.Asn370_Tyr371del inframe deletion NM_003661.3:c.1164_1169delTTATAA NM_145343.2:c.1212_1217delTTATAA inframe deletion NM_145343.3:c.1212_1217del NP_663318.1:p.Asn404_Tyr405del inframe deletion NC_000022.11:g.36266000_36266005del NC_000022.10:g.36662046_36662051del NG_023228.1:g.17930_17935del LRG_169:g.17930_17935del - Protein change
- Other names
- -
- Canonical SPDI
- NC_000022.11:36265995:ATAATTATAA:ATAA
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.03514 (ATAA)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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. |
|||
APOL1 | - | - |
GRCh38 GRCh37 |
145 | 171 |
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. |
---|---|---|---|---|
Likely risk allele; risk factor (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 24, 2023 | RCV000006454.9 | |
Pathogenic (1) |
no assertion criteria provided
|
- | RCV001003838.2 | |
Pathogenic (1) |
no assertion criteria provided
|
- | RCV001003839.2 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jan 25, 2024 | RCV001295848.9 | |
risk factor (1) |
criteria provided, single submitter
|
Mar 4, 2020 | RCV001195105.5 |
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. |
|
---|---|---|---|---|---|
risk factor
(Feb 27, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Focal segmental glomerulosclerosis 4, susceptibility to
Affected status: no, unknown, yes
Allele origin:
unknown,
biparental
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000924397.1
First in ClinVar: Jun 23, 2019 Last updated: Jun 23, 2019 |
Comment:
G2
Observation 1:
Number of individuals with the variant: 1
Age: 50-59 years
Sex: female
Comment on evidence:
G2/wild type; identical twin sister with end-stage renal disease, this individual tested as part of a living donor workup
Observation 2:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Comment on evidence:
G2/wild type; sickle cell anemia
Observation 3:
Number of individuals with the variant: 1
Age: 20-29 years
Sex: male
Comment on evidence:
G2/G2
Observation 4:
Number of individuals with the variant: 1
Age: 20-29 years
Sex: male
Comment on evidence:
G2/wild type; tested as a candidate donor for affected brother (individual in line 26)
Observation 5:
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Comment on evidence:
G1/G2; mother and brother with end stage renal disease of unknown cause, tested as part of a living donor workup.
|
|
risk factor
(Mar 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hyalinosis, Segmental Glomerular
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000197066.4
First in ClinVar: Jan 31, 2015 Last updated: Jul 03, 2020 |
Comment:
APOL1 c.1164_1169del (p.Asn388_Tyr389del), traditionally referred to as G1, has been associated with increased risk for multiple renal diseases in African Americans, particularly focal segmental glomerulosclerosis … (more)
APOL1 c.1164_1169del (p.Asn388_Tyr389del), traditionally referred to as G1, has been associated with increased risk for multiple renal diseases in African Americans, particularly focal segmental glomerulosclerosis (FSGS), as well as an increased risk for end-stage kidney disease (ESKD). This variant is common in individuals of African ancestry (14%, Genome Aggregation Database (gnomAD); rs71785313) and is present in ClinVar (ID: 6081). Several small case-control studies have reported odds ratios between 3.92-25.1 for developing FSGS/HIVAN in homozygous individuals (OR=3.92 [95% CI 1.47-9.39] for FSGS/HIVAN Ito 2014, OR=14.4 [95% CI 1.7-116.3] for HIVAN, OR=25.1 [95% CI 8.8-83.3] for FSGS Kopp 2011, OR=5.69 [95% CI not given, P<0.00001] Limou 2015). In vitro and in vivo studies provide some evidence that these alleles impact protein function (Beckerman 2017, Hayek 2017). In summary, this variant is an established risk factor for chronic kidney disease in homozygous state. (less)
Number of individuals with the variant: 36
|
|
Benign
(Feb 07, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001859790.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
Likely risk allele
(Mar 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Focal segmental glomerulosclerosis 4, susceptibility to
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518488.2
First in ClinVar: May 24, 2022 Last updated: Mar 26, 2023 |
|
|
Uncertain significance
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001484798.4
First in ClinVar: Mar 07, 2021 Last updated: Feb 20, 2024 |
Comment:
This variant, c.1164_1169del, results in the deletion of 2 amino acid(s) of the APOL1 protein (p.Asn388_Tyr389del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.1164_1169del, results in the deletion of 2 amino acid(s) of the APOL1 protein (p.Asn388_Tyr389del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs143830837, gnomAD 14%), and has an allele count higher than expected for a pathogenic variant. This variant constitutes the “G2” allele of APOL1. This allele is associated with increased risk for several forms of kidney disease in individuals of African-American ancestry when present in homozygosity or in trans with the “G1” allele (which is composed of the c.1024A>G (p.Ser342Gly) and c.1152T>G (p.Ile384Met) variants in cis). Several large case-control studies have shown a 6- to 47-fold increased risk of focal segmental glomerulosclerosis, HIV-associated nephropathy, or non-diabetic end-stage kidney disease in individuals with homozygous G1, homozygous G2, or G1 in trans with G2 alleles (PMID: 20647424, 20635188, 21997394). Similar studies in African populations have generally recapitulated these findings, but these studies are based on a relatively small number of individuals (PMID: 30340464, 25788523). A recent PheWAS study also appears to support these findings, although the risk of end-stage kidney disease may be smaller than initially assumed (closer to 3- to 4-fold; PMID: 32247630). ClinVar contains an entry for this variant (Variation ID: 6081). 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 APOL1 function (PMID: 30332315, 32675303). In summary, this variant has been shown to confer an increased risk for kidney disease, either in homozygosity or in trans with the G1 allele. However, its significance when present in heterozygosity is unclear. For these reasons, this change has been classified as a Variant of Uncertain Significance. (less)
|
|
risk factor
(Aug 13, 2010)
|
no assertion criteria provided
Method: literature only
|
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 4, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026637.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In an association analysis comparing 205 African Americans with biopsy-proven focal segmental glomerulosclerosis (FSGS4; 612551) and no family history of FSGS with 180 African American … (more)
In an association analysis comparing 205 African Americans with biopsy-proven focal segmental glomerulosclerosis (FSGS4; 612551) and no family history of FSGS with 180 African American controls, Genovese et al. (2010) identified association with FSGS of a 6-bp deletion, rs71785313, which they termed allele G2, in the last exon of the APOL1 gene. This mutation resulted in the deletion of 6 basepairs and removal of amino acids asparagine-388 (N388) and tyrosine-389 (Y389). The G2 allele was detected in 3 Yoruban participants but not in any patients from Europe, Japan, or China, all from HapMap 1000 Genomes data. The 6-bp deletion occurs at the SRA binding site in the APOL1 C-terminal helix. Genovese et al. (2010) showed that human plasma samples and recombinant APOL1 protein carrying the G2 allele lysed both SRA-negative and SRA-positive T. b. rhodesiense parasites, but not T. b. gambiense. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Focal segmental glomerulosclerosis
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162289.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Observation 2:
Number of individuals with the variant: 1
Sex: female
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Nephrotic range proteinuria
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162290.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Kidney Disease-Associated APOL1 Variants Have Dose-Dependent, Dominant Toxic Gain-of-Function. | Datta S | Journal of the American Society of Nephrology : JASN | 2020 | PMID: 32675303 |
Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function? | Bruggeman LA | American journal of physiology. Renal physiology | 2019 | PMID: 30332315 |
An African perspective on the genetic risk of chronic kidney disease: a systematic review. | George C | BMC medical genetics | 2018 | PMID: 30340464 |
A tripartite complex of suPAR, APOL1 risk variants and α(v)β(3) integrin on podocytes mediates chronic kidney disease. | Hayek SS | Nature medicine | 2017 | PMID: 28650456 |
Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. | Beckerman P | Nature medicine | 2017 | PMID: 28218918 |
Sequencing rare and common APOL1 coding variants to determine kidney disease risk. | Limou S | Kidney international | 2015 | PMID: 25993319 |
APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans. | Kasembeli AN | Journal of the American Society of Nephrology : JASN | 2015 | PMID: 25788523 |
APOL1 risk variants, race, and progression of chronic kidney disease. | Parsa A | The New England journal of medicine | 2013 | PMID: 24206458 |
APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. | Kopp JB | Journal of the American Society of Nephrology : JASN | 2011 | PMID: 21997394 |
A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9. | Genovese G | Kidney international | 2010 | PMID: 20668430 |
Association of trypanolytic ApoL1 variants with kidney disease in African Americans. | Genovese G | Science (New York, N.Y.) | 2010 | PMID: 20647424 |
Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. | Tzur S | Human genetics | 2010 | PMID: 20635188 |
click to load more click to collapse |
Text-mined citations for rs71785313 ...
HelpRecord last updated Feb 28, 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.