Submissions for variant NM_001130438.3(SPTAN1):c.6899ACCAGCTGG[3] (p.2300DQL[3])

dbSNP: rs587784440

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147656	SCV000195105	pathogenic	Developmental and epileptic encephalopathy, 5	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000189556	SCV000243199	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000696609	SCV000825175	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-10-13	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002316953	SCV000849722	pathogenic	Inborn genetic diseases	2017-05-30	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000189556	SCV000862913	pathogenic	not provided	2018-08-30	criteria provided, single submitter	clinical testing
Pediatrics, MediClubGeorgia	RCV000147656	SCV001573197	pathogenic	Developmental and epileptic encephalopathy, 5	2021-05-06	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000189556	SCV002023644	pathogenic	not provided	2022-06-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000147656	SCV002026329	likely pathogenic	Developmental and epileptic encephalopathy, 5	2017-09-01	criteria provided, single submitter	research
Mendelics	RCV000147656	SCV002519815	pathogenic	Developmental and epileptic encephalopathy, 5	2022-05-04	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000189556	SCV002818215	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000147656	SCV003924075	likely pathogenic	Developmental and epileptic encephalopathy, 5		criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV004551285	SCV004119798	pathogenic	SPTAN1-related disorder	2023-05-05	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000147656	SCV000223691	pathogenic	Developmental and epileptic encephalopathy, 5	2013-03-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV001249449	SCV001423461	not provided	Undetermined early-onset epileptic encephalopathy		no assertion provided	phenotyping only	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.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731396	SCV001984103	likely pathogenic	not specified	2020-01-24	flagged submission	clinical testing