Submissions for variant NM_022464.5(SIL1):c.1030-9G>A

gnomAD frequency: 0.00006  dbSNP: rs370290043

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000277678	SCV000329938	pathogenic	not provided	2020-07-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant creates a novel splice acceptor site (SAS), leading to the insertion of seven nucleotides into the RNA sequence, resulting in frameshift and premature truncation of translation (Anttonen et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24473200, 24176978, 27431290, 18285827, 23829326, 23062754, 27878435, 28600779, 27894351, 31130284, 32552793)
Eurofins Ntd Llc (ga)	RCV000277678	SCV000702025	pathogenic	not provided	2016-09-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001782768	SCV002022584	likely pathogenic	Marinesco-Sjögren syndrome	2021-06-15	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252076	SCV002523909	pathogenic	See cases	2020-12-07	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PM3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001782768	SCV003244158	pathogenic	Marinesco-Sjögren syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 9 of the SIL1 gene. It does not directly change the encoded amino acid sequence of the SIL1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs370290043, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of Marinesco-Sjogren syndrome (PMID: 24473200, 31130284). ClinVar contains an entry for this variant (Variation ID: 280106). Studies have shown that this variant results in activation of a de novo splice site and introduces a new termination codon (PMID: 32552793). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the SIL1 protein in which other variant(s) (p.Leu373Cysfs*33) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001782768	SCV004805025	pathogenic	Marinesco-Sjögren syndrome	2024-03-17	criteria provided, single submitter	research
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV001782768	SCV003927905	pathogenic	Marinesco-Sjögren syndrome	2023-04-01	no assertion criteria provided	clinical testing