VCV000009357.50 - ClinVar

NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His)

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.

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_000180.4(GUCY2D):c.2513G>A (p.Arg838His)

Variation ID: 9357 Accession: VCV000009357.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 8014701 (GRCh38) [ NCBI UCSC ] 17: 7918019 (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	Feb 20, 2014	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000180.4:c.2513G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000171.1:p.Arg838His	missense
NC_000017.11:g.8014701G>A
NC_000017.10:g.7918019G>A
NG_009092.1:g.17032G>A
	Q02846:p.Arg838His

... more HGVS ... less HGVS

Protein change

R838H

Other names

NP_000171.1:p.(Arg838His)

Canonical SPDI

NC_000017.11:8014700: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.

Links

ClinGen: CA226086 UniProtKB: Q02846#VAR_015373 OMIM: 600179.0008 dbSNP: rs61750173 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.
GUCY2D		-	-	GRCh38 GRCh37	-	-

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.
Cone-rod dystrophy 6	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Apr 7, 2021	RCV000009951.21
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Apr 5, 2022	RCV000084863.33
Retinal dystrophy	Pathogenic (2)	criteria provided, single submitter	Nov 14, 2018	RCV000504851.6
Progressive cone dystrophy (without rod involvement)	Uncertain significance (1)	no assertion criteria provided	Apr 1, 2018	RCV000787614.3
Cone-rod dystrophy 6 Leber congenital amaurosis 1	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV001228516.9
Retinitis pigmentosa	Pathogenic (1)	criteria provided, single submitter	Apr 1, 2021	RCV001723556.6
Cone-rod dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2023	RCV003324497.4
Cone dystrophy	Pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV001003043.4
Macular dystrophy Visual impairment	Pathogenic (1)	criteria provided, single submitter	Jul 31, 2019	RCV001271114.4

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 (Dec 07, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Cone-rod dystrophy 6 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680254.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: male Tissue: blood
Pathogenic (Nov 14, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240814.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jul 31, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Visual impairment Macular dystrophy Affected status: yes Allele origin: de novo, maternal	MNM Diagnostics Accession: SCV001451958.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021	Comment: According to ACMG Guidelines, the variant meets the following evidence of pathogenicity: PS1, PS2, PS3, PP1, PM2, PP5. Observation 1: Observation 2:
Likely pathogenic (Jan 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cone-rod dystrophy 6 Affected status: yes Allele origin: unknown	Institute of Medical Molecular Genetics, University of Zurich Accession: SCV001548155.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Publications: PubMed (1) PubMed: 33546218 Method: long-range PCR
Pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Cone-rod dystrophy 6 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760419.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (Apr 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cone-rod dystrophy 6 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001950061.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950280.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (9) PubMed: 34906470‚ 10676808‚ 11115851‚ 11565546‚ 12552567‚ 24875811‚ 26298565‚ 28041643‚ 30718709 Comment: The p.Arg838His variant in GUCY2D was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more) The p.Arg838His variant in GUCY2D was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PM1, PP1. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cone-rod dystrophy Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030413.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PP5, PM2, PM5, PM1, PS4, PP3.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Sex: male Geographic origin: Portugal
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Leber congenital amaurosis 1 Cone-rod dystrophy 6 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: SCV001400917.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 12552567‚ 26298565‚ 11115851‚ 24875811 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 838 of the GUCY2D protein (p.Arg838His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 838 of the GUCY2D protein (p.Arg838His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant cone-rod dystrophy (PMID: 12552567, 26298565). It has also been observed to segregate with disease in related individuals. This variant is also known as 2586G>A. ClinVar contains an entry for this variant (Variation ID: 9357). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GUCY2D protein function. Experimental studies have shown that this missense change affects GUCY2D function (PMID: 11115851). This variant disrupts the p.Arg838 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11115851, 12552567, 24875811, 26298565). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248905.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447772.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cone-rod dystrophy (present) Sex: female
Pathogenic (Apr 05, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001765959.3 First in ClinVar: Aug 05, 2021 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (gnomAD); Published functional studies suggest a damaging effect (dominant negative effect with a higher activity compared to wild type) … (more) Not observed in large population cohorts (gnomAD); Published functional studies suggest a damaging effect (dominant negative effect with a higher activity compared to wild type) (Wilkie et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28041643, 25082885, 23563732, 18487367, 22183351, 22968130, 24480840, 11115851, 25283059, 24875811, 15175914, 26298565, 29061346, 28181551, 25515582, 10676808, 11565546, 22194653, 29555955, 31456290, 32821499, 32036094, 32581362, 34048777, 32811265, 12552567, 33691693) (less)
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinal dystrophy Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598721.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 11565546 Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: South East Asian
Pathogenic (Feb 01, 2003)	no assertion criteria provided Method: literature only	CONE-ROD DYSTROPHY 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030172.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 19, 2017	Publications: PubMed (2) PubMed: 10676808‚ 12552567 Comment on evidence: In a patient with cone-rod dystrophy-6 (CORD6; 601777), Weigell-Weber et al. (2000) detected a G-to-A transition of the GCGC stretch at position 2586 in exon … (more) In a patient with cone-rod dystrophy-6 (CORD6; 601777), Weigell-Weber et al. (2000) detected a G-to-A transition of the GCGC stretch at position 2586 in exon 13 of the GUCY2D gene, resulting in a conservative arg838-to-his (R838H) substitution. In 8 affected members of a Caucasian American family with cone dystrophy, Udar et al. (2003) identified the R838H mutation in the GUCY2D gene. The mutation was not found in 5 unaffected family members or 200 control chromosomes. (less)
Pathogenic (Sep 01, 2016)	no assertion criteria provided Method: clinical testing	Cone-rod dystrophy 6 Affected status: yes Allele origin: unknown, inherited	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Accession: SCV000804657.2 First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018	Observation 1: Number of individuals with the variant: 2 Observation 2: Number of individuals with the variant: 1
Uncertain significance (Apr 01, 2018)	no assertion criteria provided Method: research	Progressive cone dystrophy (without rod involvement) Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926598.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
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: SCV001955988.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV001969079.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	cone dystrophy Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161100.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000116999.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_GC1:c.2513G>A
click to load more click to collapse

Comment:

The p.Arg838His variant in GUCY2D was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PM1, PP1. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 838 of the GUCY2D protein (p.Arg838His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant cone-rod dystrophy (PMID: 12552567, 26298565). It has also been observed to segregate with disease in related individuals. This variant is also known as 2586G>A. ClinVar contains an entry for this variant (Variation ID: 9357). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GUCY2D protein function. Experimental studies have shown that this missense change affects GUCY2D function (PMID: 11115851). This variant disrupts the p.Arg838 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11115851, 12552567, 24875811, 26298565). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

Not observed in large population cohorts (gnomAD); Published functional studies suggest a damaging effect (dominant negative effect with a higher activity compared to wild type) (Wilkie et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28041643, 25082885, 23563732, 18487367, 22183351, 22968130, 24480840, 11115851, 25283059, 24875811, 15175914, 26298565, 29061346, 28181551, 25515582, 10676808, 11565546, 22194653, 29555955, 31456290, 32821499, 32036094, 32581362, 34048777, 32811265, 12552567, 33691693)

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
The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.	Peter VG	PNAS nexus	2023	PMID: 36909829
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906470
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases.	Maggi J	International journal of molecular sciences	2021	PMID: 33546218
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.	Carss KJ	American journal of human genetics	2017	PMID: 28041643
GUCY2D mutations in a Chinese cohort with autosomal dominant cone or cone-rod dystrophies.	Jiang F	Documenta ophthalmologica. Advances in ophthalmology	2015	PMID: 26298565
GUCY2D- or GUCA1A-related autosomal dominant cone-rod dystrophy: is there a phenotypic difference?	Zobor D	Retina (Philadelphia, Pa.)	2014	PMID: 24875811
Identification of GUCY2D gene mutations in CORD5 families and evidence of incomplete penetrance.	Udar N	Human mutation	2003	PMID: 12552567
Clustering and frequency of mutations in the retinal guanylate cyclase (GUCY2D) gene in patients with dominant cone-rod dystrophies.	Payne AM	Journal of medical genetics	2001	PMID: 11565546
Functional characterization of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity in patients with autosomal dominant cone-rod dystrophy.	Wilkie SE	Human molecular genetics	2000	PMID: 11115851
Codons 837 and 838 in the retinal guanylate cyclase gene on chromosome 17p: hot spots for mutations in autosomal dominant cone-rod dystrophy?	Weigell-Weber M	Archives of ophthalmology (Chicago, Ill. : 1960)	2000	PMID: 10676808
click to load more click to collapse

Text-mined citations for rs61750173 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61750173 ...