Submissions for variant NM_000548.5(TSC2):c.5024C>A (p.Pro1675Gln)

dbSNP: rs45483392

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644091	SCV000765781	pathogenic	Tuberous sclerosis 2	2022-03-15	criteria provided, single submitter	clinical testing	This variant disrupts the p.Pro1675 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9302281, 9463313, 11520734, 12111193, 15024740, 21520333, 22867869). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1675 of the TSC2 protein (p.Pro1675Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 21520333; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 535873). 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 expected to disrupt TSC2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000984876	SCV001132687	likely pathogenic	Tuberous sclerosis syndrome	2019-12-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000644091	SCV002041013	likely pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV005000444	SCV005621880	likely pathogenic	not provided	2024-10-16	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual tested at Athena Diagnostics with clinical features associated with this gene. Multiple missense variants at this codon, including at least one considered to be pathogenic or likely pathogenic, have been reported in individuals with clinical features associated with this gene, suggesting this variant may also cause disease. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein.