rs387907282
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_152296.5(ATP1A3):c.2431T>C(p.Ser811Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_152296.5 missense
Scores
Clinical Significance
Conservation
Publications
- alternating hemiplegia of childhood 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- ATP1A3-associated neurological disorderInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
- cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
- developmental and epileptic encephalopathy 99Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
- dystonia 12Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
- encephalopathy, acute, infection-inducedInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- alternating hemiplegia of childhoodInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- complex neurodevelopmental disorderInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP1A3 | NM_152296.5 | c.2431T>C | p.Ser811Pro | missense_variant | Exon 18 of 23 | ENST00000648268.1 | NP_689509.1 | |
ATP1A3 | NM_001256214.2 | c.2470T>C | p.Ser824Pro | missense_variant | Exon 18 of 23 | NP_001243143.1 | ||
ATP1A3 | NM_001256213.2 | c.2464T>C | p.Ser822Pro | missense_variant | Exon 18 of 23 | NP_001243142.1 | ||
ATP1A3 | XM_047438862.1 | c.2341T>C | p.Ser781Pro | missense_variant | Exon 18 of 23 | XP_047294818.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP1A3 | ENST00000648268.1 | c.2431T>C | p.Ser811Pro | missense_variant | Exon 18 of 23 | NM_152296.5 | ENSP00000498113.1 | |||
ENSG00000285505 | ENST00000644613.1 | n.2431T>C | non_coding_transcript_exon_variant | Exon 18 of 25 | ENSP00000494711.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Alternating hemiplegia of childhood 2 Pathogenic:1
- -
Dystonia 12 Pathogenic:1
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 811 of the ATP1A3 protein (p.Ser811Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alternating hemiplegia of childhood (PMID: 22842232, 26297560, 26410222). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 37109). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A3 protein function. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 22842232). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at