rs368986242
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong
The NM_206933.4(USH2A):āc.997T>Cā(p.Ser333Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.997T>C | p.Ser333Pro | missense_variant | 6/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.997T>C | p.Ser333Pro | missense_variant | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.997T>C | p.Ser333Pro | missense_variant | 6/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.997T>C | p.Ser333Pro | missense_variant | 6/21 | 1 | |||
USH2A | ENST00000674083.1 | c.997T>C | p.Ser333Pro | missense_variant | 6/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 250972Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135610
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461672Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34AN XY: 727136
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74446
ClinVar
Submissions by phenotype
Retinal dystrophy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 22, 2017 | - - |
Uncertain significance, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Retinitis pigmentosa 39 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 07, 2017 | - - |
USH2A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 08, 2023 | The USH2A c.997T>C variant is predicted to result in the amino acid substitution p.Ser333Pro. This variant along with a splice site variant has been reported in a patient with retinitis pigmentosa (Xu et al. 2014. PMID: 24938718), in a patient with Usher syndrome in trans to a missense and in cis to a truncating variant (Kuang et al. 2018. PubMed ID: 30390381), and in additional patients with retinitis pigmentosa or hearing loss (Table S2, Liu et al. 2020. PubMed ID: 33090715; Liu et al. 2022. PubMed ID: 35106950). This variant is reported in 0.17% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-216498793-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 11, 2022 | Variant summary: USH2A c.997T>C (p.Ser333Pro) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 250972 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00014 vs 0.011), allowing no conclusion about variant significance. c.997T>C has been reported in the literature as a non-informative genotype in multiple individuals of East Asian ethnicity undergoing genetic evaluations for retinitis pigmentosa and/or hearing loss/Usher syndrome (example, Liu_2012, Zu_2014, Kuang_2020, Zhu_2021, Liu_2022). One of these families demonstrated the segregation of a variant in a different gene (SNRNP200) as the cause of autosomal dominant retinitis pigmentosa and called this variant as a "false heterozygous" (Liu_2012) (ACMG BP5). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. At-least two reports of co-occurrence in cis with another pathogenic variant have been reported (USH2A c.2187C>A, p.Cys729*), providing supporting evidence for a benign role (Kuang_2021, Zhu_2021) (ACMG BP2). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at