Submissions for variant NM_014140.4(SMARCAL1):c.2070+2dup

gnomAD frequency: 0.00009  dbSNP: rs762716070

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001386134	SCV001586260	pathogenic	Schimke immuno-osseous dysplasia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the SMARCAL1 gene. It does not directly change the encoded amino acid sequence of the SMARCAL1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs762716070, gnomAD 0.01%). This variant has been observed in individuals with clinical features of Schimke immuno-osseous dysplasia (PMID: 25943327, 27577878, 30784191). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2070+2insT and c.2070+2_3insT. ClinVar contains an entry for this variant (Variation ID: 1073210). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 27577878). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001386134	SCV002814536	pathogenic	Schimke immuno-osseous dysplasia	2022-03-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001729911	SCV003918211	pathogenic	not provided	2023-04-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, including skipping of exon 12 (Carroll et al., 2015); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect; This variant is associated with the following publications: (PMID: 25943327, 27577878, 30784191)
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001729911	SCV001977749	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729911	SCV001980636	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001386134	SCV002076319	pathogenic	Schimke immuno-osseous dysplasia	2020-07-13	no assertion criteria provided	clinical testing