rs542652468

Variant names:

• chr19-41986177-G-A
• rs542652468
• NM_152296.5:c.410C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-41986177-G-A
• chr19-41986177-G-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.410C>T​(p.Ser137Phe) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S137Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.97

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]

ENSG00000285505 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity AT1A3_HUMAN there are 5 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 chr19-41986177-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in the ATP1A3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 6.3327 (above the threshold of 3.09). Trascript score misZ: 9.1232 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.937
• PP5: Variant 19-41986177-G-A is Pathogenic according to our data. Variant chr19-41986177-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 161122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41986177-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.410C>T	p.Ser137Phe	missense_variant	Exon 5 of 23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.449C>T	p.Ser150Phe	missense_variant	Exon 5 of 23		NP_001243143.1
ATP1A3	NM_001256213.2	c.443C>T	p.Ser148Phe	missense_variant	Exon 5 of 23		NP_001243142.1
ATP1A3	XM_047438862.1	c.320C>T	p.Ser107Phe	missense_variant	Exon 5 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.410C>T	p.Ser137Phe	missense_variant	Exon 5 of 23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.410C>T		non_coding_transcript_exon_variant	Exon 5 of 25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alternating hemiplegia of childhood 2 Pathogenic:1

Mar 07, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was previously identified as pathogenic in an affected individual with alternating hemiplegia of childhood (AHC) (referenced as p.Ser137Phe, PMID:22842232). There is one report of the variant as pathogenic in ClinVar (Variation ID: 161122). There are two additional reports of a different amino acid substitution at the same residue (p.Ser150Tyr) in individuals affected with AHC (PMID:22842232). Functional characterization of the p.Ser150Tyr variant demonstrated impaired ATPase activity relative to the reference (PMID 24631656). The ATP1A3 gene is highly intolerant to missense variants and the p.Ser150 residue is highly conserved among eukaryotes. In silico algorithms predict the damaging effect on protein function. This variant is not present in any of the population allele frequency databases, thus it is presumed to be rare. Based on the combined evidence, the variant is classified as pathogenic. -

Dystonia 12 Pathogenic:1

Aug 13, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser137 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22842232). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with alternating hemiplegia of childhood (PMID: 22842232, 26297560, 26410222). ClinVar contains an entry for this variant (Variation ID: 161122). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 137 of the ATP1A3 protein (p.Ser137Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. -

not provided Pathogenic:1

Sep 26, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; the S137F mutant protein had normal expression but reduced enzyme activity compared with wild type (Heinzen et al., 2012); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31623504, 29286531, 24291144, 22842232, 29396171) -

Seizure;C0678230:Epicanthus;C1836542:Depressed nasal bridge;C3278923:Ventriculomegaly;C4021808:Abnormal earlobe morphology Pathogenic:1

Jun 22, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;D;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	M;M;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	.;D;.;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;.;D;D;.
Sift4G	Pathogenic	0.0010	.;D;D;D;D;.
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.84, 0.95, 0.84, 0.84
MutPred		0.73		Loss of disorder (P = 0.0301);Loss of disorder (P = 0.0301);.;.;.;.;
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.93
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs542652468; hg19: chr19-42490329;