19-41970539-C-T

Position:

• chr19-41970539-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.2267G>A​(p.Arg756His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R756C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 7.82

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41970540-G-A is described in Lovd as [Pathogenic].
• 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, 0.987
• PP5: Variant 19-41970539-C-T is Pathogenic according to our data. Variant chr19-41970539-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41970539-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-41970539-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.2267G>A	p.Arg756His	missense_variant	17/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.2306G>A	p.Arg769His	missense_variant	17/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.2300G>A	p.Arg767His	missense_variant	17/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.2177G>A	p.Arg726His	missense_variant	17/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2267G>A	p.Arg756His	missense_variant	17/23		NM_152296.5	ENSP00000498113

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455136 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 723816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ATP1A3: PS2, PM2, PS4:Moderate, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2024	Reported in patients with fever-triggered paroxysmal encephalopathy and weakness (PMID: 22924536, 25533962, 28647130); Published functional studies demonstrate impairment of protein folding and temperature instability (PMID: 36462665); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36703223, 36484864, 33057194, 36339296, 35982159, 24793181, 29396171, 25533962, 28382329, 28500446, 28647130, 30862413, 31269555, 31959558, 28348125, 32637629, 32466254, 34342181, 30542205, 31031587, 35047275, 22924536, 24523486, 28441826, 25996915, 38685976, 36462665) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Dystonia 12 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000161134 / PMID: 22924536) and different missense changes at the same codon (p.Arg756Cys, p.Arg756Leu, p.Arg756Ser / ClinVar ID: VCV000425189, VCV001705555 / PMID: 27634470, 28647130 / 3billion dataset) have been reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	TIDEX, University of British Columbia	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 30, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg756 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26400718, 27268479, 27634470, 27726050, 29066118, 29397530). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 161134). This missense change has been observed in individual(s) with rapid onset dystonia-parkinsonism (PMID: 22924536, 24793181, 25996915, 28441826, 28500446). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 756 of the ATP1A3 protein (p.Arg756His). -

Alternating hemiplegia of childhood 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Nov 29, 2018	This variant has been previously reported as a heterozygous change in multiple patients with neurological presentations consistent with an ATP1A3-related disorder (PMID: 22924536, 28382329, 28500446, 28647130). This variant is commonly referred to in the literature as p.Arg756His due to use of a different reference transcript (NM_152296). It has been reported as a likely pathogenic or pathogenic change by multiple clinical diagnostic laboratories in ClinVar (variant ID: 161134). The c.2306G>A (p.Arg769His) variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.2306G>A (p.Arg769His) variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 08, 2017	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Jul 27, 2020

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2016

- -

ATP1A3-associated neurological disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ATP1A3-associated neurological disorder (MONDO:0700002). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and has been commonly observed as de novo in individuals with rapid onset dystonia-parkinsonism, alternating hemiplegia or fever-triggered paroxysmal encephalopathy and weakness (ClinVar, DECIPHER, PMID: 34342181, PMID: 35047275). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Mar 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;D;T;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.7	.;D;.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.98, 0.99, 0.97, 0.97
MutPred		0.93		Loss of methylation at R756 (P = 0.1238);Loss of methylation at R756 (P = 0.1238);.;.;.;
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.66
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs606231435; hg19: chr19-42474691;