rs201153410
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000541.5(SAG):c.577C>T(p.Arg193Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,613,944 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R193R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000541.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SAG | NM_000541.5 | c.577C>T | p.Arg193Ter | stop_gained | 8/16 | ENST00000409110.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SAG | ENST00000409110.6 | c.577C>T | p.Arg193Ter | stop_gained | 8/16 | 5 | NM_000541.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000132 AC: 33AN: 249074Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135116
GnomAD4 exome AF: 0.000166 AC: 243AN: 1461636Hom.: 0 Cov.: 31 AF XY: 0.000164 AC XY: 119AN XY: 727110
GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152308Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15AN XY: 74476
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 19, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.Arg193*) in the SAG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SAG are known to be pathogenic (PMID: 9452120, 15234147, 22665972). This variant is present in population databases (rs201153410, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with Oguchi disease (PMID: 9452120, 22419846). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41895). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed with a deletion variant on the opposite allele (in trans) in a patient with Oguchi disease in published literature (Huang et al., 2012); This variant is associated with the following publications: (PMID: 15295660, 24265693, 25525159, 9452120, 25307992, 22419846, 21922265, 21151602, 17070587, 31054281, 31980526, 31589614) - |
Oguchi disease-2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Medical Molecular Genetics Department, National Research Center | Dec 01, 2019 | - - |
Oguchi disease-1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Oguchi disease-1 (MIM#258100) and retinitis pigmentosa 47 (MIM#613758). (I) 0106 - This gene is associated with autosomal recessive disease. Autosomal dominant retinitis pigmentosa has also been reported as a founder mutation (PMID: 33047631). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (42 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in both homozygous and compound heterozygous state in individuals with Oguchi disease (ClinVar, PMID: 9452120, 22419846). It has also been reported in individuals with retinitis pigmentosa (PMID: 21151602). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Retinitis pigmentosa 47 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 15, 2023 | This variant was identified as compound heterozygous with NM_000541.5:c.733G>A._x000D_ Criteria applied: PVS1, PM2_SUP, PM3_SUP - |
Retinitis pigmentosa 47;C4551824:Oguchi disease-1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 05, 2021 | - - |
Oguchi disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 30, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at