rs1553192091

Positions:

• chr1-116395247-C-A
• chr1-116395247-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The ENST00000295598.10(ATP1A1):​c.1798C>A​(p.Pro600Thr) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P600A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A1 ENST00000295598.10 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.90

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

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 9) in uniprot entity AT1A1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000295598.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-116395247-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 545678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A1. . Gene score misZ 6.2154 (greater than the threshold 3.09). Trascript score misZ 8.228 (greater than threshold 3.09). GenCC has associacion of gene with hypomagnesemia, seizures, and intellectual disability 2, charcot-marie-tooth disease, axonal, type 2DD.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811
• PP5: Variant 1-116395247-C-A is Pathogenic according to our data. Variant chr1-116395247-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545679.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-116395247-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A1	NM_000701.8	c.1798C>A	p.Pro600Thr	missense_variant	13/23	ENST00000295598.10	NP_000692.2
ATP1A1-AS1	NR_027646.1	n.401-2221G>T		intron_variant, non_coding_transcript_variant
ATP1A1	NM_001160233.2	c.1798C>A	p.Pro600Thr	missense_variant	13/23		NP_001153705.1
ATP1A1	NM_001160234.2	c.1705C>A	p.Pro569Thr	missense_variant	13/23		NP_001153706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A1	ENST00000295598.10	c.1798C>A	p.Pro600Thr	missense_variant	13/23	1	NM_000701.8	ENSP00000295598	P4
ATP1A1-AS1	ENST00000675607.1	n.385+5649G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-marie-tooth disease, axonal, type 2DD Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 28, 2018

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro600 amino acid residue in ATP1A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29499166). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ATP1A1 function (PMID: 29499166). 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 not expected to disrupt ATP1A1 protein function. ClinVar contains an entry for this variant (Variation ID: 545679). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 29499166). 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 proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 600 of the ATP1A1 protein (p.Pro600Thr). -

Charcot-Marie-Tooth disease type 2A2 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Oct 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.96	D;.;.
Vest4		0.69
MutPred		0.58		Gain of phosphorylation at P600 (P = 0.0827);Gain of phosphorylation at P600 (P = 0.0827);.;
MVP		0.89
MPC		2.7
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.76
gMVP		0.97

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: rs1553192091; hg19: chr1-116937869;