rs61749664
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The ENST00000254854.5(GUCY2D):c.121C>T(p.Leu41Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,513,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
GUCY2D
ENST00000254854.5 missense
ENST00000254854.5 missense
Scores
2
4
13
Clinical Significance
Conservation
PhyloP100: 0.367
Genes affected
GUCY2D (HGNC:4689): (guanylate cyclase 2D, retinal) This gene encodes a retina-specific guanylate cyclase, which is a member of the membrane guanylyl cyclase family. Like other membrane guanylyl cyclases, this enzyme has a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, this enzyme is not activated by natriuretic peptides. Mutations in this gene result in Leber congenital amaurosis and cone-rod dystrophy-6 diseases. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.84
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GUCY2D | NM_000180.4 | c.121C>T | p.Leu41Phe | missense_variant | 2/20 | ENST00000254854.5 | NP_000171.1 | |
GUCY2D | XM_011523816.2 | c.121C>T | p.Leu41Phe | missense_variant | 1/19 | XP_011522118.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GUCY2D | ENST00000254854.5 | c.121C>T | p.Leu41Phe | missense_variant | 2/20 | 1 | NM_000180.4 | ENSP00000254854 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152138Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000120 AC: 13AN: 108728Hom.: 0 AF XY: 0.000149 AC XY: 9AN XY: 60532
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GnomAD4 exome AF: 0.000170 AC: 231AN: 1360890Hom.: 0 Cov.: 32 AF XY: 0.000167 AC XY: 112AN XY: 671144
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GnomAD4 genome AF: 0.0000986 AC: 15AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74324
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 22, 2018 | The GUCY2D c.121C>T;p.Leu41Phe variant (rs61749664) has been published in the literature in at least one individual with Leber congenital amaurosis (Perrault 2000). The variant is reported in the ClinVar database (Variation ID: 98538 ) and in the Genome Aggregation Database with an overall allele frequency of 0.01% (15/135906 alleles). The leucine at codon 41 is moderately conserved across species and computational programs (PolyPhen2, SIFT) predict this variant is tolerated. However, at least one publication indicates that this protein shows reduced function (Zulliger 2015). Considering available information, the clinical significance of this variant cannot be determined with certainty. Pathogenic GUCY2D variants are causative for autosomal dominant cone-rod dystrophy or autosomal recessive Leber congenital amaurosis (OMIM#600179). References: Perrault I et al. Spectrum of retGC1 mutations in Leber's congenital amaurosis. Eur J Hum Genet. 2000 8(8):578-82. Zulliger R et al. Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to leber congenital amaurosis-1. J Biol Chem. 2015 290(6):3488-99. - |
not provided, no classification provided | literature only | Retina International | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2020 | Reported previously in the heterozygous state in two siblings with Leber congenital amaurosis and in one family with autosomal recessive retinitis pigmentosa; none of these individuals harbored a second identifiable GUCY2D variant (Perrault et al., 2000; Vallespin et al., 2007); Published functional studies are inconclusive, with both reduced binding to RD3 protein as well as normal basal activity reported (Zulliger et al., 2015; Sharon et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31626798, 29061346, 20012162, 18055816, 10951519, 19941040, 22695961, 25477517, 31574917) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Apr 26, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 30, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 41 of the GUCY2D protein (p.Leu41Phe). This variant is present in population databases (rs61749664, gnomAD 0.03%). This missense change has been observed in individual(s) with Leber congenital amaurosis or autosomal recessive retinitis pigmentosa (PMID: 10951519, 15024725, 18055816, 22695961). ClinVar contains an entry for this variant (Variation ID: 98538). 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 not expected to disrupt GUCY2D protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GUCY2D function (PMID: 11328726, 25477517). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1;C4551884:Choroidal dystrophy, central areolar, 1;C5231408:Night blindness, congenital stationary, type1i Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 28, 2021 | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2022 | - - |
Cone-rod dystrophy 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Feb 01, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of stability (P = 0.0927);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at