Submissions for variant NM_001379110.1(SLC9A6):c.370-9_370-5del

dbSNP: rs796053290

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000240849	SCV002540693	pathogenic	Christianson syndrome	2022-02-18	reviewed by expert panel	curation	The c.430-9_430-5del variant in SLC9A6 occurs in the de novo state (biological parentage confirmed) in an individual with delayed motor milestones and hypotonia (Baylor Genetics internal database)(PS2). RNA study has shown that this variant impacts splicing (PMID 27256868) (PS3). This variant has been reported to segregate in four informative meioses (PMID 27256868)(PP1_moderate). The c.430-9_430-5del variant in SLC9A6 has been observed in 2 unrelated families with Christianson syndrome (PMID 27256868, Baylor Genetics internal database) (PS4_supporting). The c.430-9_430-5del variant in SLC9A6 is absent from gnomAD (PM2_supporting). In summary The c.430-9_430-5del variant in SLC9A6 is classified as pathogenic for Christianson syndrome based on the ACMG/AMP criteria (PS2, PS3, PP1_moderate, PS4_supporting, PM2_supporting).
GeneDx	RCV000189417	SCV000243056	uncertain significance	not specified	2015-05-13	criteria provided, single submitter	clinical testing	The c.430-(9_5)delTTTTA variant has been previously reported (using alternative nomenclature of c.526-9_526-5delTTTTA), as a maternally inherited variant in an male patient (Redin et al., 2014). Several in-silico splice prediction models predict that c.430-(9_5)delTTTTA may damage or even destroy the natural splice acceptor site in intron 2, which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Diagnostic Laboratory, Strasbourg University Hospital	RCV000224024	SCV000281729	pathogenic	Intellectual disability	2014-07-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000240849	SCV000597126	likely pathogenic	Christianson syndrome	2016-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327019	SCV002630910	likely pathogenic	Inborn genetic diseases	2019-03-18	criteria provided, single submitter	clinical testing	The c.430-9_430-5delTTTTA intronic variant, located in intron 2 of the SLC9A6 gene, results from a deletion of 5 nucleotides within intron 2 of the SLC9A6 gene. This variant (described as c.526-9_526-5del) was originally reported in an individual with intellectual disability (Redin C et al. J. Med. Genet., 2014 Nov;51:724-36). In the follow-up study, this individual was described to have mild intellectual disability, microcephaly, and social interaction disabilities, and the same variant was detected in his affected maternal uncle, as well as female family members with learning disabilities and speech difficulties (Masurel-Paulet A et al. Am. J. Med. Genet. A, 2016 Aug;170:2103-10). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site. Analysis of RNA from the proband's blood revealed that the intronic deletion results in the skipping of exon 3 in about 90% of the transcripts, leading to in-frame deletion of 26 amino acids in the TM4 domain (Masurel-Paulet A et al. Am. J. Med. Genet. A, 2016 Aug;170:2103-10). In addition, this variant was not reported in the gnomAD database, with coverage at this position. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000240849	SCV004298990	pathogenic	Christianson syndrome	2022-11-01	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 207248). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 27256868). This variant is also known as c.526-9_526-5del. This variant has been observed in individual(s) with clinical features of SLC9A6-related conditions (PMID: 27256868). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the SLC9A6 gene. It does not directly change the encoded amino acid sequence of the SLC9A6 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
OMIM	RCV000240849	SCV000299334	pathogenic	Christianson syndrome	2021-08-19	no assertion criteria provided	literature only