19-41968837-C-T

Position:

• chr19-41968837-C-T

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.2767G>A​(p.Asp923Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D923Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 7.91

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 4 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 chr19-41968837-C-A is described in Lovd as [Likely_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, 0.85
• PP5: Variant 19-41968837-C-T is Pathogenic according to our data. Variant chr19-41968837-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41968837-C-T is described in Lovd as [Pathogenic]. Variant chr19-41968837-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.2767G>A	p.Asp923Asn	missense_variant	20/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.2806G>A	p.Asp936Asn	missense_variant	20/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.2800G>A	p.Asp934Asn	missense_variant	20/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.2677G>A	p.Asp893Asn	missense_variant	20/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2767G>A	p.Asp923Asn	missense_variant	20/23		NM_152296.5	ENSP00000498113

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dystonia 12 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 13, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 25, 2022	variant is absent in gnomAD and in-house DB; many publications describe cases and performed functional analyses to grade as pathogenic -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 923 of the ATP1A3 protein (p.Asp923Asn). This missense change has been observed in individual(s) with ATP1A3-related conditions (PMID: 19652145, 22924536, 23483595, 28849312). 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. ClinVar contains an entry for this variant (Variation ID: 12915). 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: 20576601). This variant disrupts the p.Asp923 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22850527, 24842602). 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. -

Alternating hemiplegia of childhood 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Oct 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012915, PS1_S). Ithas been previously reported as de novo in a similarly affected individual (PMID: 24842602, PS2_S). The variant was co-segregated with Alternating hemiplegia of childhood 2 in multiple affected family members (PMID: 23483595, PP1_P). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 19652145, 22924536, 23483595, 28849312, 24842602, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20576601, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.784, 3CNET: 0.979, PP3_P). A missense variant is a common mechanism associated with Alternating hemiplegia of childhood 2 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000161148, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -

ATP1A3-associated neurological disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 10, 2023

The ATP1A3 c.2767G>A (p.Asp923Asn) missense variant has been identified in individuals with ATP1A3-related neurologic disorders, including in a de novo state (PMID:18675996; 22924536; 23483595; 31361359; 31737037). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Three other missense changes at the same residue have been reported to be clinically significant in ClinVar. Functional evidence demonstrated that this variant impacts protein function (PMID: 20576601). This variant was identified in a de novo state. Based on the available evidence, the c.2767G>A (p.Asp923Asn) variant is classified as pathogenic for ATP1A3-associated neurological disorder. -

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome;C1868681:Dystonia 12;C3553788:Alternating hemiplegia of childhood 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2023

Published functional studies demonstrate a damaging effect (Einholm et al., 2010; Lazarov et al., 2020); Missense variants in nearby residues reported in the Human Gene Mutation Database (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19652145, 33144327, 28849312, 31737037, 18675996, 22924536, 23483595, 24123283, 31425744, 31361359, 24842602, 22850527, 20576601, 32653672, 23527305, 34042254, 33098801, 35872528) -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Jun 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;D;D;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.0	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.1	.;D;.;D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.039	.;D;.;D;D
Sift4G	Benign	0.66	.;T;T;T;T
Polyphen		0.98	D;D;.;.;.
Vest4		0.83, 0.92, 0.84
MutPred		0.76		Gain of MoRF binding (P = 0.0456);Gain of MoRF binding (P = 0.0456);.;.;.;
MVP		0.87
MPC		2.6
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.36
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs267606670; hg19: chr19-42472989; COSMIC: COSV57487334;