ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.970+5G>A

gnomAD frequency: 0.00001  dbSNP: rs372128852
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001376552 SCV000630067 pathogenic Citrullinemia 2023-12-12 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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs372128852, gnomAD 0.003%). This variant has been observed in individual(s) with classic citrullinemia (PMID: 7557970, 11941481, 16475226; Invitae). ClinVar contains an entry for this variant (Variation ID: 265962). 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. For these reasons, this variant has been classified as 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.
Revvity Omics, Revvity RCV000256325 SCV002024389 likely pathogenic Citrullinemia type I 2021-03-11 criteria provided, single submitter clinical testing
3billion RCV000256325 SCV002059126 likely pathogenic Citrullinemia type I 2022-01-03 criteria provided, single submitter clinical testing The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (PMID_11941481, ClinVar ID: VCV000265962). The variant has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (PMID: 7557970, PM3_P). In silico prediction tools predicted that this variant influenced pre-mRNA splicing, resulting in aberrant splicing (SPLICEAI: 0.92>=0.8, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000018, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252073 SCV002523077 pathogenic See cases 2022-03-29 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PS4, PM2, PM3
GeneDx RCV003324739 SCV004030542 likely pathogenic not provided 2023-03-01 criteria provided, single submitter clinical testing Published functional studies demonstrate that the variant results in 132 bp deletion in exon 13 (Kobayashi et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7557970, 32778825, 28111830)
OMIM RCV000256325 SCV000026900 pathogenic Citrullinemia type I 2002-04-01 no assertion criteria provided literature only
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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