rs587784438

Positions:

• chr9-128627422-CAGG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_001130438.3(SPTAN1):​c.6619_6621delGAG​(p.Glu2207del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTAN1 NM_001130438.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.53

Genes affected

SPTAN1 (HGNC:11273): (spectrin alpha, non-erythrocytic 1) Spectrins are a family of filamentous cytoskeletal proteins that function as essential scaffold proteins that stabilize the plasma membrane and organize intracellular organelles. Spectrins are composed of alpha and beta dimers that associate to form tetramers linked in a head-to-head arrangement. This gene encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell cycle regulation. Mutations in this gene are the cause of early infantile epileptic encephalopathy-5. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2010]

SPTAN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001130438.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-128627422-CAGG-C is Pathogenic according to our data. Variant chr9-128627422-CAGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128627422-CAGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTAN1	NM_001130438.3	c.6619_6621delGAG	p.Glu2207del	conservative_inframe_deletion	50/57	ENST00000372739.7	NP_001123910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTAN1	ENST00000372739.7	c.6619_6621delGAG	p.Glu2207del	conservative_inframe_deletion	50/57	1	NM_001130438.3	ENSP00000361824.4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 5 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Sep 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 5 (MIM#613477). Both missense variants and inframe deletions/duplications variants have been demonstrated to impair wildtype protein function (PMID: 20493457). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. However, this is a rare occurrence (PMID: 32811770). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated nucleation site of the a/b spectrin heterodimer region (PMID: 29050398). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic many times, and has been observed in multiple individuals with infantile epileptic encephalopathy or West syndrome with severe cerebral hypomyelination, spastic quadriplegia and developmental delay. In several of these individuals, the variant was confirmed to be de novo (ClinVar, PMID: 29050398, PMID: 20493457). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Fibroblasts from affected individuals and transfected mouse corticol neurons have both demonstrated protein aggregation and impaired wildtype protein function (PMID: 29050398, PMID: 20493457). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2012	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2024	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-frame deletion of one amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25631096, 20493457, 22429196, 29655203, 34489640, 35982159, 36331550, 33057194, 22258530) -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 16, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SPTAN1 protein function (PMID: 20493457, 22258530). This variant has been observed in individual(s) with early infantile epileptic encephalopathy or West syndrome (PMID: 22429196, 29050398, 20493457). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 160024). This variant is not present in population databases (ExAC no frequency). This variant, c.6619_6621del, results in the deletion of 1 amino acid(s) of the SPTAN1 protein (p.Glu2207del), but otherwise preserves the integrity of the reading frame. -

SPTAN1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2024

The SPTAN1 c.6619_6621delGAG variant is predicted to result in an in-frame deletion (p.Glu2207del). This variant was reported in individuals with West syndrome & cerebral hypomyelination/epilepsy (Saitsu et al 2010. PubMed ID: 20493457; reported as de novo c.6614_c.6616delAGG in Table S2, Lindy et al 2018. PubMed ID: 29655203). Functional studies suggest that .6619_6621delGAG led to abnormal aggregation of spectrin heterodimer (Saitsu et al 2010. PubMed ID: 20493457). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587784438; hg19: chr9-131389701;