rs886041396

Positions:

• chr19-41970482-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.2324C>T​(p.Pro775Leu) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P775R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 9.88

Genes affected

ATP1A3 (HGNC:801): (ATPase Na+/K+ transporting subunit alpha 3) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a transmembrane_region Helical (size 19) in uniprot entity AT1A3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_152296.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A3. . Gene score misZ 6.3327 (greater than the threshold 3.09). Trascript score misZ 9.1232 (greater than threshold 3.09). GenCC has associacion of gene with dystonia 12, alternating hemiplegia of childhood 2, ATP1A3-associated neurological disorder, developmental and epileptic encephalopathy 99, alternating hemiplegia of childhood, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, alternating hemiplegia of childhood 1, encephalopathy, acute, infection-induced.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 19-41970482-G-A is Pathogenic according to our data. Variant chr19-41970482-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41970482-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.2324C>T	p.Pro775Leu	missense_variant	17/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.2363C>T	p.Pro788Leu	missense_variant	17/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.2357C>T	p.Pro786Leu	missense_variant	17/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.2234C>T	p.Pro745Leu	missense_variant	17/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2324C>T	p.Pro775Leu	missense_variant	17/23		NM_152296.5	ENSP00000498113

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.2363C>T (p.Pro788Leu); This variant is associated with the following publications: (PMID: 33057194, 37541188, 35012964, 35982159, 37043503, 32684337) -
Uncertain significance, flagged submission	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 01, 2021	DNA sequence analysis of the ATP1A3 gene demonstrated a sequence change, c.2324C>T, in exon 17 that results in an amino acid change, p.Pro775Leu. This sequence change is absent in the gnomAD population database. The p.Pro775Leu change has been previously described as a de novo variant in individuals with ATP1A3-related disorders (PMID: 32684337, https://n.neurology.org/content/94/15_Supplement/1946). The p.Pro775Leu change affects a moderately conserved amino acid residue located in a domain of the ATP1A3 protein that is known to be functional. The p.Pro775Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL, CADD). The vast majority of pathogenic variants in the ATP1A3 gene are missense with many located around the p.Pro775 region. In addition, the ATP1A3 gene appears to be relatively intolerant to missense changes. Collectively this evidence suggests p.Pro775Leu is likely pathogenic, however functional studies have not been performed to prove this conclusively. -

Dystonia 12 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 16, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 775 of the ATP1A3 protein (p.Pro775Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ATP1A3-related conditions (PMID: 32684337; Invitae). This variant is also known as c.2363C>T p.Pro788Leu. ClinVar contains an entry for this variant (Variation ID: 280121). 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 with a positive predictive value of 95%. This variant disrupts the p.Pro775 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33880529). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP2,PP3,PP5. -

Developmental and epileptic encephalopathy 99 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 17, 2023	PS2, PM1, PM2, PM5, PP3, PP5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Oct 24, 2022	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;T;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.1	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.8	.;D;.;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.88, 0.88, 0.87
MutPred		0.73		Gain of catalytic residue at P775 (P = 0.0684);Gain of catalytic residue at P775 (P = 0.0684);.;.;.;
MVP		0.88
MPC		2.6
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.70
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041396; hg19: chr19-42474634;