Genetic Variant NM_000701.8:c.1798C>G (chr1-116395247-C-G) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_000701.8(ATP1A1):c.1798C>G(p.Pro600Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P600R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP1A1
NM_000701.8 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 7.90

Publications

1 publications found

Variant links:

Genes affected

ATP1A1 (HGNC:799): (ATPase Na+/K+ transporting subunit alpha 1) 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 1 subunit. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ATP1A1 links:

ATP1A1-AS1 (HGNC:28262): (ATP1A1 antisense RNA 1)

ATP1A1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000701.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-116395248-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1685248.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 1-116395247-C-G is Pathogenic according to our data. Variant chr1-116395247-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 545678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000701.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP1A1	NM_000701.8	MANE Select	c.1798C>G	p.Pro600Ala	missense	Exon 13 of 23	NP_000692.2
ATP1A1	NM_001160233.2		c.1798C>G	p.Pro600Ala	missense	Exon 13 of 23	NP_001153705.1	P05023-4
ATP1A1	NM_001160234.2		c.1705C>G	p.Pro569Ala	missense	Exon 13 of 23	NP_001153706.1	P05023-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP1A1	ENST00000295598.10	TSL:1 MANE Select	c.1798C>G	p.Pro600Ala	missense	Exon 13 of 23	ENSP00000295598.5	P05023-1
ATP1A1-AS1	ENST00000608511.6	TSL:1	n.411-2221G>C		intron	N/A
ATP1A1	ENST00000897942.1		c.1957C>G	p.Pro653Ala	missense	Exon 14 of 24	ENSP00000568001.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-tooth disease, axonal, type 2DD (3)

Charcot-Marie-Tooth disease type 2A2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.080

MetaRNN

Uncertain

0.59

MetaSVM

Uncertain

-0.015

MutationAssessor

Benign

1.5

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.034

Polyphen

0.94

Vest4

0.56

MutPred

0.62

Loss of methylation at K605 (P = 0.0502)

MVP

0.83

MPC

2.3

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.67

gMVP

0.94

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over