17-8014704-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000180.4(GUCY2D):c.2516C>T(p.Thr839Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 146,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T839R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000180.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000683 AC: 1AN: 146416Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251422Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135902
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1419720Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 705576
GnomAD4 genome AF: 0.00000683 AC: 1AN: 146416Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 71212
ClinVar
Submissions by phenotype
Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 839 of the GUCY2D protein (p.Thr839Met). 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 clinical features of GUCY2D-related conditions (PMID: 35567543, 37327959; internal data). ClinVar contains an entry for this variant (Variation ID: 98569). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GUCY2D protein function with a positive predictive value of 80%. 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. -
not provided Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at