Submissions for variant NM_003098.3(SNTA1):c.784A>C (p.Thr262Pro)

gnomAD frequency: 0.00041  dbSNP: rs200316080

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171082	SCV000050729	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Blueprint Genetics	RCV000157505	SCV000207250	likely benign	not specified	2015-11-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000171082	SCV000223647	likely benign	not provided	2019-04-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20009079, 21454796, 23465283)
Invitae	RCV000225771	SCV000287869	uncertain significance	Long QT syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 262 of the SNTA1 protein (p.Thr262Pro). This variant is present in population databases (rs200316080, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 20009079). ClinVar contains an entry for this variant (Variation ID: 180528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SNTA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SNTA1 function (PMID: 20009079). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000618960	SCV000735764	likely benign	Cardiovascular phenotype	2022-05-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224177	SCV003920496	uncertain significance	Long QT syndrome 12	2021-03-30	criteria provided, single submitter	clinical testing	SNTA1 NM_003098.2 exon 4 p.Thr262Pro (c.784A>C): This variant has been reported in the literature in one SIDS case (Cheng 2009 PMID:20009079). However, this variant is also present in 0.05% (14/25086) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/20-32000506-T-G) and is present in ClinVar (Variation ID:180528). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Functional studies have shown that this variant causes a significant depolarizing shift in inactivation, but overall was determined to not significantly perturb cardiac sodium channel function (Cheng 2009 PMID:20009079). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.