ClinVar

Description

The SPTA1 p.Asp1280Gly variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200890386) and ClinVar (classified as a VUS by Illumina). The variant was identified in control databases in 77 of 280580 chromosomes (0 homozygous) at a frequency of 0.000274 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 74 of 128400 chromosomes (freq: 0.000576), African in 2 of 24192 chromosomes (freq: 0.000083) and European (Finnish) in 1 of 25038 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, East Asian, Other, and South Asian populations. The p.Asp1280 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.