VCV000009355.46 - ClinVar

NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys)

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.

(15)

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

This variant is part of a Haplotype

NM_000180.3(GUCY2D):c.[2511G>C;2512C>T;2516C>T]

Identifiers

NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys)

Variation ID: 9355 Accession: VCV000009355.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 8014700 (GRCh38) [ NCBI UCSC ] 17: 7918018 (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 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000180.4:c.2512C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000171.1:p.Arg838Cys	missense
NC_000017.11:g.8014700C>T
NC_000017.10:g.7918018C>T
NG_009092.1:g.17031C>T
	Q02846:p.Arg838Cys

... more HGVS ... less HGVS

Protein change

R838C

Other names

Canonical SPDI

NC_000017.11:8014699: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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA226085 UniProtKB: Q02846#VAR_003437 OMIM: 600179.0006 OMIM: 600179.0007 dbSNP: rs61750172 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	1445	1480

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 (7)	criteria provided, multiple submitters, no conflicts	Mar 22, 2022	RCV000009949.22
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000084862.32
Cone dystrophy	Pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV001003042.9
Cone-rod dystrophy 6 Leber congenital amaurosis 1	Pathogenic (1)	criteria provided, single submitter	Jan 28, 2024	RCV001065465.14
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jun 18, 2019	RCV001074299.10
Choroidal dystrophy, central areolar, 1	Likely pathogenic (1)	criteria provided, single submitter	Apr 30, 2019	RCV001197374.10
Leber congenital amaurosis 1	Pathogenic (1)	criteria provided, single submitter	Apr 8, 2021	RCV001376215.9

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.
Pathogenic (Jun 18, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239872.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Likely pathogenic (Apr 30, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Choroidal dystrophy, central areolar, 1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368094.2 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cone-rod dystrophy 6 Affected status: yes Allele origin: germline	3billion Accession: SCV002318831.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (6) PubMed: 15175914‚ 26298565‚ 11565546‚ 9618177‚ 11115851‚ 18487367 Comment: The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9618177, 15175914, 26298565). The variant has been reported to co-segregate with the … (more) The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9618177, 15175914, 26298565). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 9618177, 26298565). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 11115851). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009357,VCV000811743, PMID:11565546,18487367,11565546). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.799>=0.6, 3CNET: 0.827>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: []%)(total allele frequency: dMAF: 0.00447). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Visual impairment (present) , Abnormal retinal morphology (present) , Retinal dystrophy (present)
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Leber congenital amaurosis 1 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573282.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (7) PubMed: 26298565‚ 15175914‚ 12552567‚ 11115851‚ 10951519‚ 9618177‚ 8554074 Comment: The GUCY2D c.2512C>T variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we … (more) The GUCY2D c.2512C>T variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1, PS3, PP1. Based on this evidence we have classified this variant as Pathogenic. (less)
Pathogenic (Feb 22, 2022)	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: SCV002102459.1 First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022	Comment: _x000D_ Criteria applied: PS4, PM5_STR, PM1_SUP, PM2_SUP, PP3
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cone-rod dystrophy 6 (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Suma Genomics Accession: SCV002605338.1 First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022	Method: Exome sequencing
Pathogenic (Apr 04, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001763874.3 First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a dominant negative effect with a higher activity compared to wild type (Tucker et al., 1999; Wilkie et al., 2000); In … (more) Published functional studies demonstrate a dominant negative effect with a higher activity compared to wild type (Tucker et al., 1999; 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: 12552567, 29555955, 28559085, 26747767, 30588428, 31456290, 32811265, 32821499, 22183351, 11115851, 24875811, 15175914, 26298565, 24664689, 22194653, 10430891, 11565546, 9618177, 18487367, 17041576, 34048777, 33369172) (less)
Pathogenic (Jan 28, 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: SCV001230423.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 9618177‚ 15175914‚ 26298565‚ 11115851‚ 12552567 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 838 of the GUCY2D protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 838 of the GUCY2D protein (p.Arg838Cys). This variant is present in population databases (rs61750172, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant cone-rod dystrophy (PMID: 9618177, 15175914, 26298565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9355). 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) performed at Invitae indicates that this missense variant is expected to disrupt GUCY2D protein function with a positive predictive value of 80%. 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, 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 (Sep 01, 2022)	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: SCV001248904.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: GUCY2D: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting Number of individuals with the variant: 5
Pathogenic (Feb 01, 2003)	no assertion criteria provided Method: literature only	CONE-ROD DYSTROPHY 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030170.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 19, 2017	Publications: PubMed (3) PubMed: 9618177‚ 8554074‚ 12552567 Comment on evidence: Kelsell et al. (1998) found another heterozygous mutation of the GUC2D gene in a family with cone-rod dystrophy (CORD6; 601777) with features somewhat different from … (more) Kelsell et al. (1998) found another heterozygous mutation of the GUC2D gene in a family with cone-rod dystrophy (CORD6; 601777) with features somewhat different from that of the original CORD6 family described in 600179.0005. In 3 families carrying this second mutation (arg838 to cys; R838C), affected individuals, although aware of poor vision in bright light from an early age, suffered loss of central vision in the late second or third decade, later than was found in the original family with the E837D mutation. The fundus appearance of affected members of these 3 families was, however, very similar to that of the original family. Electrophysiologic testing revealed marked loss of photopic function by the mid-teens, with scotopic function becoming compromised later. Genealogic studies failed to show a relationship between the 3 families. The R838C amino acid substitution resulted from a C-to-T transition at nucleotide 2585. Alignment of the portion of membrane-bound guanylate cyclases in this domain, represented by codons 809 to 871, showed that both glu837 and arg838 are fully conserved. In 38 affected members of a large multigenerational family from eastern Tennessee with autosomal dominant progressive cone dystrophy, originally described by Small and Gehrs (1996), Udar et al. (2003) identified the R838C mutation in the GUCY2D gene. The mutation was also detected in 2 unaffected family members, but was not found in 22 additional 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: SCV000804656.2 First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018	Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
pathogenic (-)	no assertion criteria provided Method: not provided	Cone-rod dystrophy 6 Affected status: not provided Allele origin: not provided	Department of Ophthalmology and Visual Sciences Kyoto University Accession: SCV000172507.1 First in ClinVar: Aug 08, 2014 Last updated: Aug 08, 2014	Comment: Converted during submission to Pathogenic.
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: SCV001161099.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
Pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Cone-rod dystrophy 6 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760418.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Retina International Accession: SCV000116998.1 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.2512C>T
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Comment:

The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9618177, 15175914, 26298565). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 9618177, 26298565). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 11115851). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009357,VCV000811743, PMID:11565546,18487367,11565546). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.799>=0.6, 3CNET: 0.827>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: []%)(total allele frequency: dMAF: 0.00447). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The GUCY2D c.2512C>T variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1, PS3, PP1. Based on this evidence we have classified this variant as Pathogenic.

Comment:

Published functional studies demonstrate a dominant negative effect with a higher activity compared to wild type (Tucker et al., 1999; 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: 12552567, 29555955, 28559085, 26747767, 30588428, 31456290, 32811265, 32821499, 22183351, 11115851, 24875811, 15175914, 26298565, 24664689, 22194653, 10430891, 11565546, 9618177, 18487367, 17041576, 34048777, 33369172)

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 838 of the GUCY2D protein (p.Arg838Cys). This variant is present in population databases (rs61750172, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant cone-rod dystrophy (PMID: 9618177, 15175914, 26298565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9355). 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) performed at Invitae indicates that this missense variant is expected to disrupt GUCY2D protein function with a positive predictive value of 80%. 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, 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.

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
GUCY2D mutations in a Chinese cohort with autosomal dominant cone or cone-rod dystrophies.	Jiang F	Documenta ophthalmologica. Advances in ophthalmology	2015	PMID: 26298565
Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration.	Kitiratschky VB	Investigative ophthalmology & visual science	2008	PMID: 18487367
Autosomal dominant cone-rod dystrophy with R838H and R838C mutations in the GUCY2D gene in Japanese patients.	Ito S	Japanese journal of ophthalmology	2004	PMID: 15175914
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
Spectrum of retGC1 mutations in Leber's congenital amaurosis.	Perrault I	European journal of human genetics : EJHG	2000	PMID: 10951519
Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy.	Kelsell RE	Human molecular genetics	1998	PMID: 9618177
Clinical study of a large family with autosomal dominant progressive cone degeneration.	Small KW	American journal of ophthalmology	1996	PMID: 8554074

Text-mined citations for rs61750172 ...

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_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61750172 ...