Submissions for variant NM_201384.3(PLEC):c.13471A>G (p.Thr4491Ala)

gnomAD frequency: 0.00011  dbSNP: rs782756146

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726265	SCV000343264	uncertain significance	not provided	2017-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000402032	SCV000721389	likely benign	not specified	2017-07-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001039102	SCV001202614	uncertain significance	Epidermolysis bullosa simplex 5B, with muscular dystrophy; Epidermolysis bullosa simplex, Ogna type; Epidermolysis bullosa simplex 5C, with pyloric atresia; Autosomal recessive limb-girdle muscular dystrophy type 2Q; Epidermolysis bullosa simplex with nail dystrophy	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 4518 of the PLEC protein (p.Thr4518Ala). This variant is present in population databases (rs782756146, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. ClinVar contains an entry for this variant (Variation ID: 288999). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Athena Diagnostics Inc	RCV000726265	SCV001879979	uncertain significance	not provided	2022-05-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726265	SCV003817889	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165766	SCV003870943	uncertain significance	Inborn genetic diseases	2023-01-26	criteria provided, single submitter	clinical testing	The c.13552A>G (p.T4518A) alteration is located in exon 33 (coding exon 32) of the PLEC gene. This alteration results from a A to G substitution at nucleotide position 13552, causing the threonine (T) at amino acid position 4518 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.