rs796053290

Variant names:

• chrX-135998094-CTTTAT-C
• rs796053290
• NM_001379110.1:c.370-9_370-5delTTTTA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP1_Moderate PM2_Supporting PS4_Supporting PS3 PS2

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA318538/MONDO:0010278/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC9A6 NM_001379110.1 splice_region, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 3.11
• Publications: 2 publications found

Genes affected

SLC9A6 (HGNC:11079): (solute carrier family 9 member A6) This gene encodes a sodium-hydrogen exchanger that is amember of the solute carrier family 9. The encoded protein localizes to early and recycling endosomes and may be involved in regulating endosomal pH and volume. Defects in this gene are associated with X-linked syndromic cognitive disability, Christianson type. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

SLC9A6 Gene-Disease associations (from GenCC):

• Christianson syndrome

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1	c.370-9_370-5delTTTTA		splice_region_variant, intron_variant	Intron 3 of 17	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.370-13_370-9delTTTAT		intron_variant	Intron 3 of 17	4	NM_001379110.1	ENSP00000487486.2
SLC9A6	ENST00000370695.8	c.526-13_526-9delTTTAT		intron_variant	Intron 2 of 15	1		ENSP00000359729.4
SLC9A6	ENST00000370698.7	c.430-13_430-9delTTTAT		intron_variant	Intron 2 of 15	1		ENSP00000359732.3
SLC9A6	ENST00000370701.6	c.370-13_370-9delTTTAT		intron_variant	Intron 3 of 16	1		ENSP00000359735.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Christianson syndrome Pathogenic:4

Feb 18, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: 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). -

Aug 19, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). 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 also known as c.526-9_526-5del. ClinVar contains an entry for this variant (Variation ID: 207248). 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). For these reasons, this variant has been classified as Pathogenic. -

Jan 27, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Mar 18, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Intellectual disability Pathogenic:1

Jul 25, 2014

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 13, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs796053290; hg19: chrX-135080253;