Submissions for variant NM_000541.5(SAG):c.944+5G>A

gnomAD frequency: 0.00007  dbSNP: rs374048703

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002449	SCV001160391	uncertain significance	not specified	2019-04-11	criteria provided, single submitter	clinical testing	The SAG c.944+5G>A variant (rs374048703), to our knowledge, is not reported in the medical literature or gene-specific databases. However, ARUP Laboratories has detected this variant in an individual with an alternative molecular explanation for disease. The variant is reported in the general population with an overall allele frequency of 0.01% (32/279094 alleles) in the Genome Aggregation Database. This is an intronic variant in a highly conserved nucleotide, the +5 position is critical in RNA splicing, and computational analyses (Alamut v.2.11) predict that this variant alters splicing by weakening the upstream donor. However, given the lack of clinical and functional data, the significance of the variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044386	SCV001208181	uncertain significance	not provided	2024-12-20	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the SAG gene. It does not directly change the encoded amino acid sequence of the SAG protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374048703, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SAG-related conditions. ClinVar contains an entry for this variant (Variation ID: 811941). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Illumina Laboratory Services, Illumina	RCV001139655	SCV001299831	uncertain significance	Oguchi disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001139656	SCV001299832	uncertain significance	Retinitis pigmentosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199363	SCV001370462	uncertain significance	Retinitis pigmentosa 47	2019-08-21	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
GeneDx	RCV001044386	SCV002757185	uncertain significance	not provided	2022-11-25	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge