Submissions for variant NM_001903.5(CTNNA1):c.965C>T (p.Ser322Leu)

dbSNP: rs1554085478

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000801850	SCV000941648	likely pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 322 of the CTNNA1 protein (p.Ser322Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pattern dystrophy and/or retinal dystrophy (PMID: 28041643, 33137351; Invitae). ClinVar contains an entry for this variant (Variation ID: 437999). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CTNNA1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics	RCV000504773	SCV001239380	likely pathogenic	Retinal dystrophy	2018-05-15	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197574	SCV001368353	uncertain significance	Patterned macular dystrophy 2	2020-04-02	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP4.
GeneDx	RCV000801850	SCV001985732	uncertain significance	not provided	2022-11-29	criteria provided, single submitter	clinical testing	Identified in individuals referred for hereditary cancer multi-gene panel testing (Clark et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32051609, 32581362, 28041643, 33137351)
Ambry Genetics	RCV002383975	SCV002693877	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	The p.S322L variant (also known as c.965C>T), located in coding exon 6 of the CTNNA1 gene, results from a C to T substitution at nucleotide position 965. The serine at codon 322 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504773	SCV000598758	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research