19-40397529-G-T

Variant names:

• chr19-40397529-G-T
• rs200033507
• NM_181882.3:c.823C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_181882.3(PRX):​c.823C>A​(p.Leu275Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,544,562 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L275L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (6 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:6 O:1
• Conservation: PhyloP100: -0.179
• Publications: 4 publications found

Genes affected

PRX (HGNC:13797): (periaxin) This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy. [provided by RefSeq, Jul 2008]

PRX Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4F

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016151339).
• BP6: Variant 19-40397529-G-T is Benign according to our data. Variant chr19-40397529-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216836.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00105 (160/152352) while in subpopulation NFE AF = 0.00213 (145/68020). AF 95% confidence interval is 0.00185. There are 1 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181882.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	NM_181882.3	MANE Select	c.823C>A	p.Leu275Ile	missense	Exon 7 of 7	NP_870998.2
	PRX	NM_001411127.1		c.1108C>A	p.Leu370Ile	missense	Exon 7 of 7	NP_001398056.1
	PRX	NM_020956.2		c.*1028C>A		3_prime_UTR	Exon 6 of 6	NP_066007.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	ENST00000324001.8	TSL:1 MANE Select	c.823C>A	p.Leu275Ile	missense	Exon 7 of 7	ENSP00000326018.6
	PRX	ENST00000291825.11	TSL:1	c.*1028C>A		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6
	PRX	ENST00000674005.2		c.1108C>A	p.Leu370Ile	missense	Exon 7 of 7	ENSP00000501261.1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000935 AC: 133 AN: 142232 AF XY: 0.000875

Gnomad AFR exome AF: 0.000299

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.000723

GnomAD4 exome AF: 0.00179 AC: 2490 AN: 1392210 Hom.: 6 Cov.: 35 AF XY: 0.00168 AC XY: 1155 AN XY: 686700

African (AFR) AF: 0.000189 AC: 6 AN: 31672

American (AMR) AF: 0.0000836 AC: 3 AN: 35892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25068

East Asian (EAS) AF: 0.00 AC: 0 AN: 35888

South Asian (SAS) AF: 0.00 AC: 0 AN: 79822

European-Finnish (FIN) AF: 0.000261 AC: 11 AN: 42174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.00225 AC: 2423 AN: 1078608

Other (OTH) AF: 0.000813 AC: 47 AN: 57836

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.000939 AC XY: 70 AN XY: 74512

African (AFR) AF: 0.000288 AC: 12 AN: 41596

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00213 AC: 145 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00103

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000276 AC: 1

ESP6500EA AF: 0.000928 AC: 7

ExAC AF: 0.000497 AC: 55

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:2

Sep 13, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PRX c.823C>A; p.Leu275Ile variant (rs200033507), is reported in the literature in individuals affected with Charcot-Marie-Tooth (CMT) disease or hereditary motor neuropathy, but did not segregate with disease in at least two families, suggesting the variant is not causative for disease (Antoniadi 2015, Hoyer 2014). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 216836), and is found in the non-Finnish European population with an allele frequency of 0.22% (153/69,546 alleles) in the Genome Aggregation Database. The leucine at codon 275 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. Thus, based on available information, the clinical significance of the p.Leu275Ile variant cannot be determined with certainty. References: Antoniadi T et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. 2015 Sep 21;16:84. Hoyer et al. Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. Biomed Res Int. 2014 2014: 210401.

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRX: BP1

Jan 04, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 24, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25025039, 26257172, 26392352, 32376792)

Charcot-Marie-Tooth disease type 4F Uncertain:1 Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Likely benign and reported on 07-24-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Inborn genetic diseases Uncertain:1

Oct 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.823C>A (p.L275I) alteration is located in exon 7 (coding exon 4) of the PRX gene. This alteration results from a C to A substitution at nucleotide position 823, causing the leucine (L) at amino acid position 275 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Tip-toe gait Uncertain:1

Apr 27, 2021

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

not specified Benign:1

Dec 05, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRX-related disorder Benign:1

Aug 03, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: 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).

Charcot-Marie-Tooth disease type 4 Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.18
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.052
Sift	Benign	0.54	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.18
MVP		0.41
MPC		0.55
ClinPred		0.033	T
GERP RS		1.2
Varity_R		0.053
gMVP		0.087
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200033507; hg19: chr19-40903436;