Submissions for variant NM_201384.3(PLEC):c.4220C>T (p.Ala1407Val)

gnomAD frequency: 0.00001  dbSNP: rs548430154

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000604760	SCV000720795	likely benign	not specified	2017-07-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810548	SCV000950761	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	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1434 of the PLEC protein (p.Ala1434Val). This variant is present in population databases (rs548430154, 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: 510552). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The valine 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.
CeGaT Center for Human Genetics Tuebingen	RCV000999095	SCV001155539	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PLEC: PM2, BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000604760	SCV005202700	uncertain significance	not specified	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: PLEC c.4301C>T (p.Ala1434Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 211160 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLEC causing PLEC-Related Disorders, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4301C>T in individuals affected with PLEC-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 510552). Based on the evidence outlined above, the variant was classified as uncertain significance.