VCV000283615.52 - ClinVar

NM_000180.4(GUCY2D):c.129_134del (p.Leu44_Leu45del)

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.

(13)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(4); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000180.4(GUCY2D):c.129_134del (p.Leu44_Leu45del)

Variation ID: 283615 Accession: VCV000283615.52

Type and length

Deletion, 6 bp

Location

Cytogenetic: 17p13.1 17: 8003171-8003176 (GRCh38) [ NCBI UCSC ] 17: 7906489-7906494 (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	Jan 13, 2017	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000180.4:c.129_134del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000171.1:p.Leu44_Leu45del	inframe deletion
NM_000180.3:c.129_134del6
NM_000180.3:c.129_134delTCTGCT
NC_000017.11:g.8003176_8003181del
NC_000017.10:g.7906494_7906499del
NG_009092.1:g.5507_5512del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:8003170:CTGCTTCTGCT:CTGCT

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.

0.00220 (CTGCT)

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

Links

ClinGen: CA8365473 dbSNP: rs552184470 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	1451	1486

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 specified	Uncertain significance (1)	criteria provided, single submitter	Jan 1, 2019	RCV000784899.4
Abnormal electroretinogram Nystagmus	Likely pathogenic (1)	criteria provided, single submitter	Jul 11, 2014	RCV000414862.3
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Nov 1, 2018	RCV000415795.33
Choroidal dystrophy, central areolar, 1	Likely pathogenic (1)	criteria provided, single submitter	Jan 1, 2016	RCV001199370.3
Cone-rod dystrophy 6	Uncertain significance (2)	criteria provided, single submitter	May 28, 2019	RCV000989733.3
GUCY2D-related disorder	Likely benign (1)	no assertion criteria provided	Nov 1, 2019	RCV003939980.2
Cone-rod dystrophy 6 Leber congenital amaurosis 1	Likely benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001081143.9
Leber congenital amaurosis 1	Likely pathogenic (1)	criteria provided, single submitter	Jan 30, 2021	RCV001352942.2

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 (Jul 11, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormal electroretinogram Nystagmus Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492721.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Uncertain significance (Oct 13, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000335816.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 17964524 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GUCY2D Number of individuals with the variant: 2 Zygosity: Single Heterozygote Sex: mixed
Uncertain significance (Mar 28, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577499.3 First in ClinVar: May 22, 2017 Last updated: May 22, 2017	Comment: The c.129_134delTCTGCT variant in the GUCY2D gene has been reported previously in individuals with Leber congenital amaurosis or retinal dystrophy, but limited information was provided … (more) The c.129_134delTCTGCT variant in the GUCY2D gene has been reported previously in individuals with Leber congenital amaurosis or retinal dystrophy, but limited information was provided on the affected individuals (Stone et al., 2007; Sergouniotis et al., 2016). The c.129_134delTCTGCT variant causes an in-frame deletion of two Leucine residues starting at codon Leucine 44 amino acid, denoted p.Leu44_Leu45del. This amino acid deletion occurs at a position in a poly Leucine region that is not conserved. Reliable data is not available in large population cohorts to assess the frequency of the c.129_134delTCTGCT variant; however, it was observed in 176/63508 (0.277%) alleles from individuals undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.129_134delTCTGCT as a variant of uncertain significance. (less)
Uncertain significance (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000923438.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Number of individuals with the variant: 1 Sex: female Geographic origin: Iran
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Cone-rod dystrophy 6 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140277.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely pathogenic (Jan 01, 2016)	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: SCV001370469.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Likely pathogenic. This variant was inherited from a parent.
Likely pathogenic (Jan 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 1 Affected status: yes Allele origin: unknown	Institute of Medical Molecular Genetics, University of Zurich Accession: SCV001548008.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Publications: PubMed (1) PubMed: 33546218 Method: long-range PCR
Likely benign (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: SCV001020636.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Likely benign (Nov 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: SCV000493155.33 First in ClinVar: Jan 30, 2017 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001920051.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	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: SCV001969006.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Uncertain significance (Oct 30, 2023)	no assertion criteria provided Method: clinical testing	Cone-rod dystrophy 6 Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004099313.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023
Likely benign (Nov 01, 2019)	no assertion criteria provided Method: clinical testing	GUCY2D-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004750478.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Comment:

The c.129_134delTCTGCT variant in the GUCY2D gene has been reported previously in individuals with Leber congenital amaurosis or retinal dystrophy, but limited information was provided on the affected individuals (Stone et al., 2007; Sergouniotis et al., 2016). The c.129_134delTCTGCT variant causes an in-frame deletion of two Leucine residues starting at codon Leucine 44 amino acid, denoted p.Leu44_Leu45del. This amino acid deletion occurs at a position in a poly Leucine region that is not conserved. Reliable data is not available in large population cohorts to assess the frequency of the c.129_134delTCTGCT variant; however, it was observed in 176/63508 (0.277%) alleles from individuals undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.129_134delTCTGCT as a variant of uncertain significance.

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
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases.	Maggi J	International journal of molecular sciences	2021	PMID: 33546218
Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture.	Stone EM	American journal of ophthalmology	2007	PMID: 17964524
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GUCY2D	-	-	-	-

Text-mined citations for rs552184470 ...

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 Dec 07, 2024

ClinVar Genomic variation as it relates to human health

NM_000180.4(GUCY2D):c.129_134del (p.Leu44_Leu45del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs552184470 ...