rs781565158

Variant names:

• chr12-21452130-A-G
• rs781565158
• NM_024854.5:c.464A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PP3 PP5_Very_Strong BS1_Supporting

The NM_024854.5(PYROXD1):​c.464A>G​(p.Asn155Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,584,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N155N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PYROXD1 NM_024854.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.01
• Publications: 8 publications found

Genes affected

PYROXD1 (HGNC:26162): (pyridine nucleotide-disulphide oxidoreductase domain 1) This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11. [provided by RefSeq, Apr 2017]

PYROXD1 Gene-Disease associations (from GenCC):

• myofibrillar myopathy 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.744
• PP5: Variant 12-21452130-A-G is Pathogenic according to our data. Variant chr12-21452130-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 372280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000147 (21/1432516) while in subpopulation MID AF = 0.000945 (5/5292). AF 95% confidence interval is 0.000372. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYROXD1	NM_024854.5	c.464A>G	p.Asn155Ser	missense_variant	Exon 5 of 12	ENST00000240651.14	NP_079130.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYROXD1	ENST00000240651.14	c.464A>G	p.Asn155Ser	missense_variant	Exon 5 of 12	1	NM_024854.5	ENSP00000240651.9

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000473 AC: 11 AN: 232610 AF XY: 0.0000238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.0000467

Gnomad OTH exome AF: 0.000358

GnomAD4 exome AF: 0.0000147 AC: 21 AN: 1432516 Hom.: 0 Cov.: 28 AF XY: 0.0000126 AC XY: 9 AN XY: 711936

African (AFR) AF: 0.00 AC: 0 AN: 32506

American (AMR) AF: 0.00 AC: 0 AN: 41564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.00 AC: 0 AN: 38742

South Asian (SAS) AF: 0.00 AC: 0 AN: 79944

European-Finnish (FIN) AF: 0.0000756 AC: 4 AN: 52908

Middle Eastern (MID) AF: 0.000945 AC: 5 AN: 5292

European-Non Finnish (NFE) AF: 0.00000821 AC: 9 AN: 1096782

Other (OTH) AF: 0.0000507 AC: 3 AN: 59154

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 8 Pathogenic:7

Sep 27, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 27745833). In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.64 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372280 /PMID: 27745833 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 27745833). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 29, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Asn155Ser variant in PYROXD1 was identified by our study in 1 individual with myofibrillar myopathy. The variant has been reported in 11 affected individuals, segregated with disease in 5 affected relatives from 4 families (PMID: 27745833, 32037607). The presence of this variant in 8 affected homozygotes with myofibrillar myopathy increases the likelihood that the p.Asn155Ser variant is pathogenic (PMID: 30345904, 32037607, 27745833). This variant has been identified in 0.01% (3/24752) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781565158). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 372280) as pathogenic by the Undiagnosed Disease Network, NIH. In vitro functional studies provide some evidence that the p.Asn155Ser variant may impact protein function (PMID: 30345904, 27745833). However, these types of assays may not accurately represent biological function. Animal models in zebrafish have shown that this variant causes myofibrillar myopathy (PMID: 27745833). The p.Asn155Ser variant is located in a region of PYROXD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30345904). In summary, this variant meets criteria to be classified as pathogenic for myofibrillar myopathy in an autosomal recessive manner based on animal models that recapitulate the phenotpye, functional assays that report a disruption to protein function, and multiple reports of homozygous affected individuals. ACMG/AMP Criteria applied: PS3, PP1_strong, PM3, PM2_supporting, PM1_supporting (Richards 2015). -

Jul 01, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2024

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3 PS3 PM2 -

Apr 13, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 28, 2017

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant was observed in the heterozygous state in the proband's mother and father. The variant was observed in the homozygous state in the patient's similarly affected maternal aunt. -

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3+PM3_Strong+PM2+PP1 -

not provided Pathogenic:3

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies indicate that the N155S variant impairs PYROXD1 function (PMID: 27745833); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32037607, 27745833, 30345904, 30515627, 31455395, 31607746, 34426522, 33694278, 36100962, 38544359, 36920481, 34418069, 37259682, 38553017, 37895316) -

Dec 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 155 of the PYROXD1 protein (p.Asn155Ser). This variant is present in population databases (rs781565158, gnomAD 0.01%). This missense change has been observed in individual(s) with PYROXD1-related conditions (PMID: 27745833). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372280). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PYROXD1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PYROXD1 function (PMID: 27745833). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.74	D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	2.9	M;.
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.58		Gain of catalytic residue at G154 (P = 0);.;
MVP		0.36
MPC		0.57
ClinPred		0.77	D
GERP RS		4.8
Varity_R		0.82
gMVP		0.77
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781565158; hg19: chr12-21605064;