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

gnomAD frequency: 0.00001  dbSNP: rs372128852

Total submissions: 11

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	2024-01-12	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