Submissions for variant NM_000391.4(TPP1):c.532C>G (p.Pro178Ala)

dbSNP: rs149986601

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189742	SCV000243390	uncertain significance	not provided	2016-06-08	criteria provided, single submitter	clinical testing	The P178A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P178A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000189742	SCV001410697	uncertain significance	not provided	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 178 of the TPP1 protein (p.Pro178Ala). This variant is present in population databases (rs149986601, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 207552). 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 TPP1 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	RCV003362719	SCV004072331	uncertain significance	Inborn genetic diseases	2023-06-22	criteria provided, single submitter	clinical testing	The c.532C>G (p.P178A) alteration is located in exon 6 (coding exon 6) of the TPP1 gene. This alteration results from a C to G substitution at nucleotide position 532, causing the proline (P) at amino acid position 178 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001833126	SCV002094868	uncertain significance	Neuronal ceroid lipofuscinosis 2	2020-03-24	no assertion criteria provided	clinical testing