Submissions for variant NM_024854.5(PYROXD1):c.464A>G (p.Asn155Ser)

gnomAD frequency: 0.00002  dbSNP: rs781565158

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000412572	SCV000746660	pathogenic	Myofibrillar myopathy 8	2017-04-28	criteria provided, single submitter	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000412572	SCV001430801	pathogenic	Myofibrillar myopathy 8	2020-05-29	criteria provided, single submitter	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).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268267	SCV001447070	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001268267	SCV001815052	pathogenic	not provided	2020-08-07	criteria provided, single submitter	clinical testing	Published functional studies indicate that the N155S variant impairs PYROXD1 function (O'Grady et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31607746, 31455395, 30345904, 30515627, 27745833, 32037607)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001268267	SCV003440973	pathogenic	not provided	2024-12-11	criteria provided, single submitter	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.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV000412572	SCV005038610	pathogenic	Myofibrillar myopathy 8	2024-03-01	criteria provided, single submitter	research	PS3+PM3_Strong+PM2+PP1
OMIM	RCV000412572	SCV000490355	pathogenic	Myofibrillar myopathy 8	2023-04-13	no assertion criteria provided	literature only