chr9-128632260-G-GGGACCAGCT

Position:

• chr9-128632260-G-GGGACCAGCT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_Very_Strong

The NM_001130438.3(SPTAN1):​c.6908_6916dupACCAGCTGG​(p.Asp2303_Leu2305dup) variant causes a disruptive inframe insertion 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: 33)
• Consequence: SPTAN1 NM_001130438.3 disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 9.59

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001130438.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-128632260-G-GGGACCAGCT is Pathogenic according to our data. Variant chr9-128632260-G-GGGACCAGCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTAN1	NM_001130438.3	c.6908_6916dupACCAGCTGG	p.Asp2303_Leu2305dup	disruptive_inframe_insertion	53/57	ENST00000372739.7	NP_001123910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTAN1	ENST00000372739.7	c.6908_6916dupACCAGCTGG	p.Asp2303_Leu2305dup	disruptive_inframe_insertion	53/57	1	NM_001130438.3	ENSP00000361824.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 5 Pathogenic:6

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	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Inframe indel variant c.6881_6882insGGACCAGCT in Exon 52 of the SPTAN1 gene that results in the amino acid substitution p.Trp2294_Asp2295insAspGlnLeu was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/ LikelyPathogenic (Variant ID: 160028). This disorder has previously been reported in the patient affected with epilepsy (Nonoda Y et.al 2012). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pediatrics, MediClubGeorgia	May 06, 2021	This variant is absent in population databases. There is two submission on Clinvar with pathogenic interpretation. This variant has been observed in individual(s) with clinical features of SCN2A-related conditions. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2022	Published functional studies suggest this variant has a dominant negative effect on neurons, however additional studies are needed to validate the functional effect of this variant (Wang et al., 2018); In-frame duplication of three amino acids in a non-repeat region; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34440880, 22656320, 29337302, 29050398, 25631096) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2018	- -

not specified Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Jan 24, 2020

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2017

The c.6908_6916dupACCAGCTGG pathogenic mutation (also known as p.D2303_L2305dup), located in coding exon 52 of the SPTAN1 gene, results from an in-frame duplication of ACCAGCTGG at nucleotide positions 6908 to 6916. This results in the duplication of 3 extra residues (DQL) between codons 2303 and 2305. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of developmental delay, intellectual disability, and microcephaly. This duplication was also reported as a de novo occurrence in a 1-year-old male with West syndrome, hypomyelination of the cerebral white matter, and impaired psychomoter development (Nonoda Y et al. Brain Dev., 2013 Mar;35:280-3). The mutation occurs in the last two spectrin repeats of the SPTAN1 protein, where several in-frame duplications and deletions have been detected in patients with West syndrome (Tohyama J et al. J. Hum. Genet., 2015 Apr;60:167-73). In addition, this alteration is predicted to be deleterious by PROVEAN in silico analysis (Choi Y et al., PLoS ONE 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

ClinVar contains an entry for this variant (Variation ID: 160028). This variant has been observed in individual(s) with West syndrome (PMID: 22656320, 29050398). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.6908_6916dup, results in the insertion of 3 amino acid(s) of the SPTAN1 protein (p.Asp2303_Leu2305dup), but otherwise preserves the integrity of the reading frame. Experimental studies have shown that this variant affects SPTAN1 function (PMID: 29050398). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. -

SPTAN1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2023

The SPTAN1 c.6908_6916dup9 variant is predicted to result in an in-frame duplication (p.Asp2303_Leu2305dup). This variant has been reported as a recurrent de novo change in multiple unrelated individuals affected with West syndrome with progressive brain atrophy and functional studies suggested that this variant causes aggregation of spectrin complexes in neurons via dominant-negative effects (Nonoda et al. 2013. PubMed ID: 22656320; Tohyama et al. 2015. PubMed ID: 25631096; Syrbe et al. 2017. PubMed ID: 29050398; Wang et al. 2018. PubMed ID: 29337302). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Undetermined early-onset epileptic encephalopathy Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Pathogenic and reported on 08-28-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587784440; hg19: chr9-131394539;