VCV000636659.26 - ClinVar

NM_000278.5(PAX2):c.226G>C (p.Gly76Arg)

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.

(6)

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 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_000278.5(PAX2):c.226G>C (p.Gly76Arg)

Variation ID: 636659 Accession: VCV000636659.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q24.31 10: 100750707 (GRCh38) [ NCBI UCSC ] 10: 102510464 (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	Jul 27, 2019	Oct 8, 2024	Mar 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000278.5:c.226G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000269.3:p.Gly76Arg	missense
NM_000278.4:c.226G>C
NM_001304569.2:c.319G>C	NP_001291498.1:p.Gly107Arg	missense
NM_003987.5:c.226G>C	NP_003978.3:p.Gly76Arg	missense
NM_003988.5:c.226G>C	NP_003979.2:p.Gly76Arg	missense
NM_003989.5:c.226G>C	NP_003980.3:p.Gly76Arg	missense
NM_003990.3:c.226G>C
NM_003990.4:c.226G>C
NM_003990.5:c.226G>C	NP_003981.3:p.Gly76Arg	missense
NC_000010.11:g.100750707G>C
NC_000010.10:g.102510464G>C
NG_008680.2:g.19999G>C

... more HGVS ... less HGVS

Protein change

G76R, G107R

Other names

Canonical SPDI

NC_000010.11:100750706:G:C

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.

Links

dbSNP: rs79555199 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.
PAX2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	477	499

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.
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 30, 2022	RCV000788556.5
Focal segmental glomerulosclerosis 7	Likely pathogenic (1)	criteria provided, single submitter	Sep 5, 2022	RCV002290036.4
Renal coloboma syndrome	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003388597.2
See cases	Likely pathogenic (1)	criteria provided, single submitter	Mar 23, 2023	RCV003325974.1
PAX2-related disorder	Likely pathogenic (1)	no assertion criteria provided	Jun 25, 2024	RCV004738005.1

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 (May 25, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000927709.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 Comment: Patient analyzed with Cystic Kidney Disease Panel
Likely pathogenic (Sep 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Focal segmental glomerulosclerosis 7 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581888.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM1, PM5, PM2_SUP, PP1, PP3	Number of individuals with the variant: 1
Likely pathogenic (Nov 30, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002759249.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32776440, Wilson2020[preprint]) (less)
Likely pathogenic (Mar 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: germline	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust Accession: SCV003853426.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023	Publications: PubMed (1) PubMed: 32776440 Clinical Features: Hyperuricemia (present)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal coloboma syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004100337.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: The missense variant p.G76R in PAX2 (NM_000278.5) has been previously reported in a similarly affected family (Stevenson M et al,2020). It has been submitted to … (more) The missense variant p.G76R in PAX2 (NM_000278.5) has been previously reported in a similarly affected family (Stevenson M et al,2020). It has been submitted to ClinVar as Likely Pathogenic though detials are not available for independent assessment.The p.G76R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.G76R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 76 of PAX2 is conserved in all mammalian species. The nucleotide c.226 in PAX2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less) Clinical Features: Renal dysplasia (present)
Likely pathogenic (Jun 25, 2024)	no assertion criteria provided Method: clinical testing	PAX2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005359899.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PAX2 c.226G>C variant is predicted to result in the amino acid substitution p.Gly76Arg. This variant has been reported in multiple affected individuals from one … (more) The PAX2 c.226G>C variant is predicted to result in the amino acid substitution p.Gly76Arg. This variant has been reported in multiple affected individuals from one family with renal coloboma syndrome and segregated with disease (Stevenson et al. 2020. PubMed ID: 32776440). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32776440, Wilson2020[preprint])

Comment:

The missense variant p.G76R in PAX2 (NM_000278.5) has been previously reported in a similarly affected family (Stevenson M et al,2020). It has been submitted to ClinVar as Likely Pathogenic though detials are not available for independent assessment.The p.G76R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.G76R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 76 of PAX2 is conserved in all mammalian species. The nucleotide c.226 in PAX2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

The PAX2 c.226G>C variant is predicted to result in the amino acid substitution p.Gly76Arg. This variant has been reported in multiple affected individuals from one family with renal coloboma syndrome and segregated with disease (Stevenson et al. 2020. PubMed ID: 32776440). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely 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
Whole genome sequence analysis identifies a PAX2 mutation to establish a correct diagnosis for a syndromic form of hyperuricemia.	Stevenson M	American journal of medical genetics. Part A	2020	PMID: 32776440

Text-mined citations for rs79555199 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000278.5(PAX2):c.226G>C (p.Gly76Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs79555199 ...