NM_000283.4:c.811G>A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3PP5
The NM_000283.4(PDE6B):c.811G>A(p.Glu271Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,906 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000283.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000558 AC: 14AN: 251076Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135854
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461552Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727090
GnomAD4 genome AF: 0.0000656 AC: 10AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6AN XY: 74494
ClinVar
Submissions by phenotype
Retinal dystrophy Pathogenic:2Uncertain:1
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not provided Pathogenic:1Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 271 of the PDE6B protein (p.Glu271Lys). This variant is present in population databases (rs374156343, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 27353947, 30646425; internal data). 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: 497466). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDE6B protein function. For these reasons, this variant has been classified as Pathogenic. -
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PDE6B-related disorder Pathogenic:1
The PDE6B c.811G>A variant is predicted to result in the amino acid substitution p.Glu271Lys. This variant has been reported in the homozygous and compound heterozygous states in individuals with retinal disease (Tiwari et al. 2016. PubMed ID: 27353947; Koyanagi et al. 2019. PubMed ID: 31213501; Palmowski-Wolfe et al. 2019. PubMed ID: 30646425; Karali et al. 2022. PubMed ID: 36460718). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. Given the evidence, we interpret this variant as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at