chr6-79493707-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1
The NM_001122769.3(LCA5):c.764G>A(p.Arg255Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001122769.3 missense
Scores
Clinical Significance
Conservation
Publications
- LCA5-related retinopathyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Leber congenital amaurosis 5Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- Leber congenital amaurosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- severe early-childhood-onset retinal dystrophyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LCA5 | NM_001122769.3 | c.764G>A | p.Arg255Gln | missense_variant | Exon 4 of 8 | ENST00000369846.9 | NP_001116241.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LCA5 | ENST00000369846.9 | c.764G>A | p.Arg255Gln | missense_variant | Exon 4 of 8 | 1 | NM_001122769.3 | ENSP00000358861.4 | ||
LCA5 | ENST00000392959.5 | c.764G>A | p.Arg255Gln | missense_variant | Exon 5 of 9 | 1 | ENSP00000376686.1 | |||
LCA5 | ENST00000467898.3 | c.764G>A | p.Arg255Gln | missense_variant | Exon 4 of 7 | 5 | ENSP00000474463.1 | |||
ENSG00000231533 | ENST00000652956.1 | n.469+12267C>T | intron_variant | Intron 3 of 3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 250620 AF XY: 0.0000369 show subpopulations
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461304Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 726954 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74292 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 255 of the LCA5 protein (p.Arg255Gln). This variant is present in population databases (rs727503995, gnomAD 0.01%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 24265693). ClinVar contains an entry for this variant (Variation ID: 167256). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
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LCA5-related disorder Uncertain:1
The LCA5 c.764G>A variant is predicted to result in the amino acid substitution p.Arg255Gln. This variant has been reported as an additional allele in an individual with Leber congenital amaurosis that could be explained by variants in a different gene (Eisenberger et al. 2013. PubMed ID: 24265693). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at