ClinVar Miner

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

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Total submissions: 12
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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

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