Submissions for variant NM_001903.5(CTNNA1):c.1385C>T (p.Pro462Leu)

gnomAD frequency: 0.00004  dbSNP: rs977288078

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806478	SCV000946482	uncertain significance	not provided	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 462 of the CTNNA1 protein (p.Pro462Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CTNNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 651177). Invitae Evidence 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 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 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	RCV002388520	SCV002698295	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	The p.P462L variant (also known as c.1385C>T), located in coding exon 9 of the CTNNA1 gene, results from a C to T substitution at nucleotide position 1385. The proline at codon 462 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
PreventionGenetics, part of Exact Sciences	RCV003396411	SCV004104451	uncertain significance	CTNNA1-related disorder	2023-07-08	criteria provided, single submitter	clinical testing	The CTNNA1 c.1385C>T variant is predicted to result in the amino acid substitution p.Pro462Leu. This variant has been observed in a cohort of individual with gastric or breast cancer (Supplemental Table 1, Clark et al. 2020. PubMed ID: 32051609). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-138240126-C-T); and, it is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/651177/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003472389	SCV004211278	uncertain significance	Patterned macular dystrophy 2	2024-03-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000806478	SCV005439337	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals referred for hereditary cancer multi-gene panel testing (PMID: 32051609); This variant is associated with the following publications: (PMID: 32051609)