ClinVar Miner

Submissions for variant NM_000050.4(ASS1):c.970+5G>A (rs372128852)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001376552 SCV000630067 likely pathogenic Citrullinemia 2019-06-14 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the ASS1 gene. It does not directly change the encoded amino acid sequence of the ASS1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs372128852, ExAC 0.001%). This variant has been reported as homozygous and in combination with another ASS1 variant in individuals affected with classic citrullinemia (PMID: 7557970, 11941481). ClinVar contains an entry for this variant (Variation ID: 265962). Exon skipping has been observed in RNA analysis of cells from a patient homozygous for this variant (PMID: 7557970). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing also suggest that this variant may disrupt the consensus splice site. 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.
Fulgent Genetics,Fulgent Genetics RCV000256325 SCV000893798 likely pathogenic Citrullinemia type I 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000256325 SCV001163599 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000256325 SCV001338489 pathogenic Citrullinemia type I 2020-04-02 criteria provided, single submitter clinical testing Variant summary: ASS1 c.970+5G>A alters a 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 that the variant abolishes or weakens a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Kobayashi_1995). The variant allele was found at a frequency of 1.6e-05 in 251104 control chromosomes (gnomAD). c.970+5G>A has been reported in the literature in multiple individuals affected with Citrullinemia Type I (e.g. Kobayashi_1995, Haberle_2002, Gao_2003, Diez-Fernandez_2016). These data indicate that the variant is very likely to be associated with disease. Four other 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000256325 SCV000323100 pathogenic Citrullinemia type I 2016-09-01 no assertion criteria provided literature only
Counsyl RCV000256325 SCV000790673 likely pathogenic Citrullinemia type I 2017-03-31 no assertion criteria provided clinical testing

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