rs606231443

Positions:

• chr19-41968846-GGAC-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.2755_2757delGTC​(p.Val919del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.18

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 13 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
• PM4: Nonframeshift variant in NON repetitive region in NM_152296.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-41968846-GGAC-G is Pathogenic according to our data. Variant chr19-41968846-GGAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41968846-GGAC-G is described in Lovd as [Pathogenic]. Variant chr19-41968846-GGAC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.2755_2757delGTC	p.Val919del	conservative_inframe_deletion	20/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.2794_2796delGTC	p.Val932del	conservative_inframe_deletion	20/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.2788_2790delGTC	p.Val930del	conservative_inframe_deletion	20/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.2665_2667delGTC	p.Val889del	conservative_inframe_deletion	20/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2755_2757delGTC	p.Val919del	conservative_inframe_deletion	20/23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.2755_2757delGTC		non_coding_transcript_exon_variant	20/25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dystonia 12 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 11, 2022

This variant, c.2755_2757del, results in the deletion of 1 amino acid(s) of the ATP1A3 protein (p.Val919del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with alternating hemiplegia of childhood (PMID: 22842232; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 161147). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy 99 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The observed inframe c.2755_2757del(p.Val919del) variant in ATP1A3 gene has been reported in an individual affected with ATP1A3 related disease (Heinzen EL, et. al., 2012). The p.Val919del variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. This p.Val919del causes deletion of amino acid Valine at position 919. Additional functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs606231443; hg19: chr19-42472998;