Submissions for variant NM_004637.5(RAB7A):c.167T>C (p.Leu56Pro) (rs775104487)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235278	SCV000293055	uncertain significance	not provided	2017-04-06	criteria provided, single submitter	clinical testing	The L56P variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L56P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not highly conserved. 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	RCV000698626	SCV000827304	uncertain significance	Charcot-Marie-Tooth disease type 2B	2018-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with proline at codon 56 of the RAB7A protein (p.Leu56Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs775104487, ExAC 0.01%). This variant has not been reported in the literature in individuals with RAB7A-related disease. ClinVar contains an entry for this variant (Variation ID: 245880). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.