Submissions for variant NM_020956.2(PRX):c.*1779T>C (rs149715830)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000228501	SCV000291762	uncertain significance	Charcot-Marie-Tooth disease type 4	2020-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine with alanine at codon 525 of the PRX protein (p.Val525Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs149715830, ExAC 0.2%). This variant has been reported in 3 individuals affected with peripheral neuropathy (PMID: 24627108, 26392352). ClinVar contains an entry for this variant (Variation ID: 242179). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0. The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on PRX function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina	RCV001094584	SCV000413235	uncertain significance	Charcot-Marie-Tooth disease, demyelinating, type 4F	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000658836	SCV000514286	likely benign	not provided	2020-10-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24627108, 26392352, 32376792)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000658836	SCV000703932	uncertain significance	not provided	2018-05-01	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000658836	SCV000780632	uncertain significance	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre	RCV000789549	SCV001335853	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000431721	SCV001475998	benign	not specified	2020-06-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000658836	SCV001715533	uncertain significance	not provided	2020-08-06	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000789549	SCV000928905	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000658836	SCV001554397	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PRX p.Val525Ala variant was identified in 3 of 950 proband chromosomes (frequency: 0.0032) from individuals or families with Inherited Peripheral Neuropathies and was not identified in 4492 control chromosomes from healthy individuals (Schabhüttl_2014_PMID: 24627108; Antoniadi_2015_PMID: 26392352). The variant was also identified in dbSNP (ID: rs149715830) and in ClinVar where there are conflicting interpretations of pathogenicity for Charcot-Marie-Tooth disease type 4 from five submitters: 4x uncertain significance (Invitae, Illumina Clinical Services Laboratory, EGL Genetic Diagnostics, and Praxis fuer Humangenetik Tuebingen) and 1x likely benign by GeneDx. The variant was identified in control databases in 193 of 282028 chromosomes at a frequency of 0.000684 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 160 of 128602 chromosomes (freq: 0.001244), Other in 7 of 7216 chromosomes (freq: 0.00097), European (Finnish) in 12 of 25114 chromosomes (freq: 0.000478), African in 8 of 24778 chromosomes (freq: 0.000323), Ashkenazi Jewish in 2 of 10336 chromosomes (freq: 0.000194), Latino in 3 of 35432 chromosomes (freq: 0.000085) and South Asian in 1 of 30616 chromosomes (freq: 0.000033); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Val525 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics,Academic Medical Center	RCV000658836	SCV001923428	likely benign	not provided		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000658836	SCV001955925	likely benign	not provided		no assertion criteria provided	clinical testing