ClinVar Genomic variation as it relates to human health
NM_024854.5(PYROXD1):c.285+1G>A
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024854.5(PYROXD1):c.285+1G>A
Variation ID: 372278 Accession: VCV000372278.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p12.1 12: 21445467 (GRCh38) [ NCBI UCSC ] 12: 21598401 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 7, 2017 Feb 14, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024854.5:c.285+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001350912.2:c.72+1G>A splice donor NM_001350913.2:c.-419+1G>A splice donor NC_000012.12:g.21445467G>A NC_000012.11:g.21598401G>A NG_053196.1:g.12864G>A - Protein change
- Other names
- IVS3DS, G-A, +1
- Canonical SPDI
- NC_000012.12:21445466:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00011
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PYROXD1 | - | - |
GRCh38 GRCh37 |
349 | 635 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 2, 2023 | RCV000412640.4 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV001390403.7 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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Myofibrillar myopathy 8
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001524934.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: curation
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Myofibrillar myopathy 8
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003922304.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
The heterozygous c.285+1G>A variant in PYROXD1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (NC_000012.12:g.21461062T>G), in one … (more)
The heterozygous c.285+1G>A variant in PYROXD1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (NC_000012.12:g.21461062T>G), in one individual with limb girdle myopathy. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (NC_000012.12:g.21461062T>G). The c.285+1G>A variant in PYROXD1 has been reported in six individuals with myofibrillar myopathy 8 (PMID: 27745833, PMID: 33333461, PMID: 32528171), but has been identified in 0.02% (4/25598) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs369083786). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 372278) and has been interpreted as pathogenic by Invitae, Baylor Genetics, and OMIM, and as likely pathogenic by GeneDx. Of these six previously reported individuals, four were homozygotes (PMID: 32528171) and 1 was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 27745833, ClinVar ID: 372279), and, in addition, the patient identified by our study was a compound heterozygote who carried a variant of uncertain significance (NC_000012.12:g.21461062T>G) in trans, which increases the likelihood that the c.285+1G>A variant is pathogenic. RT-PCR analysis performed on affected muscle tissue showed evidence of exon skipping of exon 3 (PMID: 27745833). Exon 3 (NM_024854.5) is in-frame with 120 nucleotides (40 codons). This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the PYROXD1 gene is an established disease mechanism in autosomal recessive myofibrillar myopathy 8. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive myofibrillar myopathy 8. ACMG/AMP Criteria applied: PVS1_Moderate, PM3_Strong, PS3_Moderate (Richards 2015). (less)
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Likely pathogenic
(May 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001815618.2
First in ClinVar: Sep 08, 2021 Last updated: May 20, 2023 |
Comment:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a … (more)
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27745833, 31455395, 32528171, 34694888, 33333461) (less)
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Pathogenic
(Jan 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001592127.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 3 of the PYROXD1 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 3 of the PYROXD1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs369083786, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with early-onset myopathy (PMID: 27745833, 31455395). 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: 372278). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 27745833). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 19, 2016)
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no assertion criteria provided
Method: literature only
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MYOPATHY, MYOFIBRILLAR, 8
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000490353.1
First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017 |
Comment on evidence:
In 2 brothers, born of unrelated parents of European descent (family A), with myofibrillar myopathy-8 (MFM8; 617258), O'Grady et al. (2016) identified compound heterozygous mutations … (more)
In 2 brothers, born of unrelated parents of European descent (family A), with myofibrillar myopathy-8 (MFM8; 617258), O'Grady et al. (2016) identified compound heterozygous mutations in the PYROXD1 gene: a G-to-A transition in intron 3 (c.285+1G-A, NM_024854), and a c.1116G-C transversion in exon 10, resulting in a gln372-to-his (Q372H; 617220.0002) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The splice site mutation was found at a low frequency (4.295 x 10(-5)) in the ExAC database, whereas the Q372H variant was not found in ExAC. Analysis of patient cells confirmed that the c.285+1G-A variant caused abnormal splicing. Patient skeletal muscle and fibroblasts showed decreased levels of PYROXD1. In vitro functional expression assays showed that the Q372H mutant was unable to rescue a growth defect in mutant yeast, indicating impaired reductase activity compared to wildtype. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical, histological, and genetic characterization of PYROXD1-related myopathy. | Lornage X | Acta neuropathologica communications | 2019 | PMID: 31455395 |
Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization. | O'Grady GL | American journal of human genetics | 2016 | PMID: 27745833 |
Text-mined citations for rs369083786 ...
HelpRecord last updated Mar 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.