1-215674103-T-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_SupportingPM3_StrongPP4
This summary comes from the ClinGen Evidence Repository: The c.13808A>C (p.His4603Pro) variant in USH2A is a missense variant predicted to cause a substitution of histidine by a proline at amino acid 4603. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00000084 (4/1179986 alleles) in the european non-finnish population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.34, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in 1 proband with retinal disease and hearing loss (which was diagnosed at the age of 49 years old) in trans with a pathogenic variant by family testing (PMID:28157192). Besides, this variant has been detected in 4 individuals with USH2A associated conditions which is highly specific for disease (PP4). All individuals were heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (c.2299del, p.(Glu767Serfs*21); c.5118G>A, p.(Trp1706*); c.2276G>T, p.(Cys759Phe) and c.5573-834A>G; PM3 3 points, Blueprint Genetics internal evidence SCV001239096.1) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive USH2A condition (isolated RP) based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PM3_Strong and PP4. (ClinGen Hearing Loss VCEP specifications version 2, 20.11.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA183350/MONDO:0019501/005
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.13808A>C | p.His4603Pro | missense_variant | Exon 63 of 72 | 1 | NM_206933.4 | ENSP00000305941.3 | ||
USH2A | ENST00000674083.1 | c.13808A>C | p.His4603Pro | missense_variant | Exon 63 of 73 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461772Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727192
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Usher syndrome Pathogenic:1
The c.13808A>C (p.His4603Pro) variant in USH2A is a missense variant predicted to cause a substitution of histidine by a proline at amino acid 4603. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00000084 (4/1179986 alleles) in the european non-finnish population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.34, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in 1 proband with retinal disease and hearing loss (which was diagnosed at the age of 49 years old) in trans with a pathogenic variant by family testing (PMID: 28157192). Besides, this variant has been detected in 4 individuals with USH2A associated conditions which is highly specific for disease (PP4). All individuals were heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (c.2299del, p.(Glu767Serfs*21); c.5118G>A, p.(Trp1706*); c.2276G>T, p.(Cys759Phe) and c.5573-834A>G; PM3 3 points, Blueprint Genetics internal evidence SCV001239096.1) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive USH2A condition (isolated RP) based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PM3_Strong and PP4. (ClinGen Hearing Loss VCEP specifications version 2, 20.11.2024). -
not provided Pathogenic:1
This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 4603 of the USH2A protein (p.His4603Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 28157192; 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: 178937). 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 USH2A protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Retinal dystrophy Pathogenic:1
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not specified Uncertain:1
The His4603Pro variant in USH2A has not been reported in individuals with hearin g loss or in large population studies. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional d ata is needed to determine the clinical significance of this variant. -
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at