ClinVar Miner

Submissions for variant NM_002103.5(GYS1):c.1890G>A (p.Ala630=)

gnomAD frequency: 0.00019  dbSNP: rs142457302
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001048161 SCV001212151 uncertain significance Glycogen storage disease due to muscle and heart glycogen synthase deficiency 2022-10-17 criteria provided, single submitter clinical testing This sequence change affects codon 630 of the GYS1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GYS1 protein. This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GYS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 845147). 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 is not likely to affect RNA splicing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479272 SCV004223519 uncertain significance not specified 2023-11-08 criteria provided, single submitter clinical testing Variant summary: GYS1 c.1890G>A (p.Ala630Ala) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251062 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1890G>A in individuals affected with Glycogen Storage Disease Due To Muscle And Heart Glycogen Synthase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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