rs61749668
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong
The NM_000180.4(GUCY2D):c.307G>A(p.Glu103Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000175 in 1,469,548 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E103V) has been classified as Pathogenic.
Frequency
Consequence
NM_000180.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GUCY2D | NM_000180.4 | c.307G>A | p.Glu103Lys | missense_variant | 2/20 | ENST00000254854.5 | |
GUCY2D | XM_011523816.2 | c.307G>A | p.Glu103Lys | missense_variant | 1/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GUCY2D | ENST00000254854.5 | c.307G>A | p.Glu103Lys | missense_variant | 2/20 | 1 | NM_000180.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152004Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.000191 AC: 252AN: 1317544Hom.: 0 Cov.: 34 AF XY: 0.000198 AC XY: 129AN XY: 649942
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152004Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74264
ClinVar
Submissions by phenotype
Leber congenital amaurosis 1 Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Likely pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 30, 2020 | - - |
not provided Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17964524, 34048777, 32581362, 18055820, 31704230, 28041643, 29178642) - |
not provided, no classification provided | literature only | Retina International | - | - - |
Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 103 of the GUCY2D protein (p.Glu103Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive GUCY2D-related conditions (PMID: 28041643, 29178642; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 98590). 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 with a negative predictive value of 80%. This variant disrupts the p.Glu103 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21602930, 34048777). 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. - |
Cone dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at