VCV000001078.31 - ClinVar

NM_015272.5(RPGRIP1L):c.685G>A (p.Ala229Thr)

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.

(20)

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.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015272.5(RPGRIP1L):c.685G>A (p.Ala229Thr)

Variation ID: 1078 Accession: VCV000001078.31

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q12.2 16: 53686524 (GRCh38) [ NCBI UCSC ] 16: 53720436 (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	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_015272.5:c.685G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056087.2:p.Ala229Thr	missense
NM_001127897.4:c.685G>A	NP_001121369.1:p.Ala229Thr	missense
NM_001308334.3:c.685G>A	NP_001295263.1:p.Ala229Thr	missense
NM_001330538.2:c.685G>A	NP_001317467.1:p.Ala229Thr	missense
NM_015272.4:c.685G>A
NC_000016.10:g.53686524C>T
NC_000016.9:g.53720436C>T
NG_008991.2:g.22336G>A
LRG_696:g.22336G>A
LRG_696t1:c.685G>A	LRG_696p1:p.Ala229Thr
LRG_696t2:c.685G>A	LRG_696p2:p.Ala229Thr
	Q68CZ1:p.Ala229Thr

... more HGVS ... less HGVS

Protein change

A229T

Other names

RPGRIP1L, ALA229THR (rs61747071)
p.A229T:GCT>ACT
c.685G>A

Canonical SPDI

NC_000016.10:53686523:C:T

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.

0.05331 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.03564

Exome Aggregation Consortium (ExAC) 0.03750

The Genome Aggregation Database (gnomAD) 0.04969

Trans-Omics for Precision Medicine (TOPMed) 0.05185

1000 Genomes Project 0.05331

1000 Genomes Project 30x 0.05668

Links

ClinGen: CA114735 UniProtKB: Q68CZ1#VAR_066477 OMIM: 610937.0013 dbSNP: rs61747071 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.
RPGRIP1L		-	-	GRCh38 GRCh37	1851	1876

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.
Retinitis pigmentosa in ciliopathies, modifier of	risk factor (1)	no assertion criteria provided	Jun 1, 2009	RCV000001133.12
Familial aplasia of the vermis	Conflicting interpretations of pathogenicity (2)	no assertion criteria provided	Sep 16, 2020	RCV000035002.15
not specified	Benign (7)	criteria provided, multiple submitters, no conflicts	Dec 20, 2021	RCV000114223.26
Nephronophthisis	not provided (1)	no classification provided	-	RCV000234815.13
Meckel syndrome, type 5	Benign (1)	criteria provided, single submitter	Mar 6, 2018	RCV000332989.14
Familial aplasia of the vermis Meckel-Gruber syndrome	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV000473873.20
Nephronophthisis 8	Benign (1)	criteria provided, single submitter	Mar 6, 2018	RCV001094311.13
Joubert syndrome 7	Benign (3)	criteria provided, multiple submitters, no conflicts	Jun 10, 2021	RCV001094370.17
not provided	Benign (2)	criteria provided, single submitter	-	RCV001705578.10
Focal segmental glomerulosclerosis	Benign (1)	criteria provided, single submitter	Sep 9, 2022	RCV002293972.9

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000312485.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Feb 13, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000231744.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RPGRIP1L Number of individuals with the variant: 1 Sex: mixed
Benign (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Joubert syndrome 7 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001737344.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Sex: mixed
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005292026.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Mar 21, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000171379.9 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Nephronophthisis 8 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000397841.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Meckel syndrome, type 5 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000397840.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Joubert syndrome 7 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000397839.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Dec 20, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002051288.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: Variant summary: RPGRIP1L c.685G>A (p.Ala229Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging … (more) Variant summary: RPGRIP1L c.685G>A (p.Ala229Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.036 in 251116 control chromosomes, predominantly at a frequency of 0.11 within the African or African-American subpopulation in the gnomAD database, including 73 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 139.14 fold of the estimated maximal expected allele frequency for a pathogenic variant in RPGRIP1L causing Joubert Syndrome And Related Disorders phenotype (0.00079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Sep 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Inherited focal segmental glomerulosclerosis Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002587282.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial aplasia of the vermis Meckel-Gruber syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000556988.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024
Likely benign (-)	no assertion criteria provided Method: clinical testing	AllHighlyPenetrant (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000147780.2 First in ClinVar: Apr 04, 2014 Last updated: Jul 06, 2014	Comment: Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more) Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less) Number of individuals with the variant: 23
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Joubert syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457423.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001975035.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
risk factor (Jun 01, 2009)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA IN CILIOPATHIES, MODIFIER OF Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021283.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 19430481 Comment on evidence: Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene, a 685G-A transition, resulting in an ala229-to-thr (A229T) substitution (rs61747071), may … (more) Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene, a 685G-A transition, resulting in an ala229-to-thr (A229T) substitution (rs61747071), may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations. The 229T allele was significantly enriched among a group of 487 patients with ciliopathy and retinal pigmentosa, including LCA (204000), Senior-Loken syndrome (266900), Joubert syndrome (213300), and BBS (209900), compared to 115 patients with ciliopathy without retinal pigmentosa, including NPHP (256100) and MKS (249000) (p = 1.66 x 10(-5)). In vitro functional expression studies showed that the 229T allele had decreased ability to bind to RPGR compared to the 229A allele. (less)
pathologic (Mar 29, 2012)	no assertion criteria provided Method: curation	Joubert Syndrome and Related Disorders Affected status: not provided Allele origin: not provided	GeneReviews Accession: SCV000058641.1 First in ClinVar: May 03, 2013 Last updated: May 03, 2013	Comment: Converted during submission to Pathogenic.
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001923971.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927900.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
not provided (-)	no classification provided Method: literature only	Nephronophthisis Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000292020.2 First in ClinVar: Jul 02, 2016 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 19430481 BookShelf: NBK368475 BookShelf: NBK368475
not provided (-)	no classification provided Method: literature only	Joubert syndrome 7 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001792276.2 First in ClinVar: Aug 21, 2021 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301500 BookShelf: NBK1325 BookShelf: NBK1325
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Variant summary: RPGRIP1L c.685G>A (p.Ala229Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.036 in 251116 control chromosomes, predominantly at a frequency of 0.11 within the African or African-American subpopulation in the gnomAD database, including 73 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 139.14 fold of the estimated maximal expected allele frequency for a pathogenic variant in RPGRIP1L causing Joubert Syndrome And Related Disorders phenotype (0.00079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign.

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
Nephronophthisis-Related Ciliopathies.	Adam MP	-	2023	PMID: 27336129
Joubert Syndrome.	Adam MP	-	2017	PMID: 20301500
A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.	Khanna H	Nature genetics	2009	PMID: 19430481
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RPGRIP1L	-	-	-	-

Text-mined citations for rs61747071 ...

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_015272.5(RPGRIP1L):c.685G>A (p.Ala229Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61747071 ...