ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5951C>A (p.Pro1984His) (rs146733308)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723619 SCV000111475 uncertain significance not provided 2013-04-19 criteria provided, single submitter clinical testing
GeneDx RCV000723619 SCV000242659 benign not provided 2021-03-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000716817 SCV000847661 benign History of neurodevelopmental disorder 2019-03-07 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Fulgent Genetics,Fulgent Genetics RCV000764282 SCV000895301 uncertain significance Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001080157 SCV001008820 likely benign Early infantile epileptic encephalopathy with suppression bursts 2020-11-13 criteria provided, single submitter clinical testing
New York Genome Center RCV001281471 SCV001468779 uncertain significance Seizures 2019-06-02 criteria provided, single submitter clinical testing The SCN1A c.5951C>A (p.Pro1984His) variant identified substitutes a highly conserved Proline for Histidine at amino acid 1973/1999 (coding exon 29/29). In silico algorithms predict this variant to be Deleterious (Provean; score:-6.60) and Damaging (SIFT; score:0.00) to the function of the canonical transcript. The c.5951C>A (p.Pro1984His) variant has been reported in ClinVar as a Variant of Uncertain Significance (VarID: 93661), and has been reported a single time in a large cohort study of pediatric patients with drug resistant epilepsy [PMID: 29353705], with no patient specific phenotype information. Given the lack of compelling information supporting its pathogenicity, the c.5951C>A (p.Pro1984His) variant identified in the SCN1A gene is reported here as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000723619 SCV001549488 likely benign not provided no assertion criteria provided clinical testing The SCN1A p.P1984H variant was not identified in the literature but was identified in dbSNP (ID: rs146733308) and ClinVar (classified as uncertain significance by GeneDx, EGL Genetic Diagnostics, and Fulgent Genetics; as likely benign by Invitae; and as benign by Ambry Genetics). The variant was identified in control databases in 61 of 282118 chromosomes at a frequency of 0.0002162, and was observed at the highest frequency in the African population in 59 of 24952 chromosomes (freq: 0.002365) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant epilepsy with febrile seizures and early infantile epileptic encephalopathy conditions associated with SCN1A variants. The p.P1984 residue is conserved in mammals and more distantly related organisms, and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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