rs121918615
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_000702.4(ATP1A2):c.2936C>T(p.Pro979Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P979R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000702.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A2 | NM_000702.4 | c.2936C>T | p.Pro979Leu | missense_variant | 21/23 | ENST00000361216.8 | |
ATP1A2 | XM_047421286.1 | c.2045C>T | p.Pro682Leu | missense_variant | 14/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A2 | ENST00000361216.8 | c.2936C>T | p.Pro979Leu | missense_variant | 21/23 | 1 | NM_000702.4 | P1 | |
ATP1A2 | ENST00000392233.7 | c.2936C>T | p.Pro979Leu | missense_variant | 21/23 | 5 | |||
ATP1A2 | ENST00000447527.1 | c.2018C>T | p.Pro673Leu | missense_variant | 14/16 | 2 | |||
ATP1A2 | ENST00000463989.1 | n.272C>T | non_coding_transcript_exon_variant | 3/4 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Migraine, familial hemiplegic, 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 25, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 16, 2023 | _x000D_ Criteria applied: PS3, PS4_MOD, PM2_SUP, PP2, PP3, PP4 - |
Familial hemiplegic migraine Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | Severe phenotype reported - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 979 of the ATP1A2 protein (p.Pro979Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial and sporadic hemiplegic migraine (PMID: 15159495, 23821026, 27790126). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12925). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP1A2 protein function. Experimental studies have shown that this missense change affects ATP1A2 function (PMID: 19372756). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2019 | Published functional studies demonstrate a damaging effect, with P979L resulting in an unstable protein at physiological temperature comparing with wild type (Tavraz et al., 2009); Not observed in large population cohorts (Lek 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: 16437583, 19673908, 28479855, 15907261, 18184292, 27790126, 23821026, 19372756, 15159495) - |
Migraine, familial hemiplegic, 2;C3549447:Alternating hemiplegia of childhood 1 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant interpreted as Pathogenic and reported on 06-11-2018 by Lab Children's National Medical Center. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at