Submissions for variant NM_000304.4(PMP22):c.178+7C>A

gnomAD frequency: 0.00111  dbSNP: rs147885521

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081441	SCV000562722	likely benign	Charcot-Marie-Tooth disease, type I	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000614118	SCV000729478	likely benign	not specified	2018-03-15	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.
CeGaT Center for Human Genetics Tuebingen	RCV000456190	SCV001151225	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PMP22: BP4, BS1
Illumina Laboratory Services, Illumina	RCV001122570	SCV001281296	benign	Hereditary liability to pressure palsies	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173928	SCV001337047	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001543104	SCV001761610	likely pathogenic	Tip-toe gait	2019-05-05	criteria provided, single submitter	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
Athena Diagnostics	RCV000614118	SCV001879480	benign	not specified	2020-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000614118	SCV004028588	likely benign	not specified	2023-07-17	criteria provided, single submitter	clinical testing	Variant summary: PMP22 c.178+7C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 150980 control chromosomes, predominantly at a frequency of 0.0024 within the Latino subpopulation in the gnomAD database (v3.1), including 1 homozygote, suggesting that the variant is likely a benign polymorphism. To our knowledge, no occurrence of c.178+7C>A in individuals affected with PMP22-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority classified the variant as benign (n=2)/likely benign (n=3), and others classified it as either VUS (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000456190	SCV004563922	likely benign	not provided	2023-11-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535491	SCV004724686	likely benign	PMP22-related disorder	2019-11-05	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).