rs1028534806

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001696.4(ATP6V1E1):c.634C>T(p.Arg212Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,712 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATP6V1E1
NM_001696.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.50

Variant links:

Genes affected

ATP6V1E1 (HGNC:857): (ATPase H+ transporting V1 subunit E1) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. This gene encodes alternate transcriptional splice variants, encoding different V1 domain E subunit isoforms. Pseudogenes for this gene have been found in the genome. [provided by RefSeq, Jul 2008]

ATP6V1E1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 22-17592721-G-A is Pathogenic according to our data. Variant chr22-17592721-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17592721-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1E1	NM_001696.4 link	c.634C>T	p.Arg212Trp	missense_variant	Exon 9 of 9	ENST00000253413.10	NP_001687.1	P36543-1Q53Y06
ATP6V1E1	NM_001039366.1 link	c.568C>T	p.Arg190Trp	missense_variant	Exon 8 of 8		NP_001034455.1	P36543-2
ATP6V1E1	NM_001039367.1 link	c.544C>T	p.Arg182Trp	missense_variant	Exon 8 of 8		NP_001034456.1	P36543-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP6V1E1	ENST00000253413.10 link	c.634C>T	p.Arg212Trp	missense_variant	Exon 9 of 9	1	NM_001696.4	ENSP00000253413.5	P36543-1
ATP6V1E1	ENST00000399798.6 link	c.568C>T	p.Arg190Trp	missense_variant	Exon 8 of 8	2		ENSP00000382696.2	P36543-2
ATP6V1E1	ENST00000399796.6 link	c.544C>T	p.Arg182Trp	missense_variant	Exon 8 of 8	2		ENSP00000382694.2	P36543-3
ATP6V1E1	ENST00000473248.1 link	n.780C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727178

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive cutis laxa type 2C

Pathogenic:4

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 22, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 212 of the ATP6V1E1 protein (p.Arg212Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cutis laxa (PMID: 27023906, 28065471). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 417760). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. 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. -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published in vitro functional studies suggest a damaging effect on glycosylation (Van Damme et al., 2017); This variant is associated with the following publications: (PMID: 27023906, 28065471) -

Cutis laxa

Pathogenic:1

Mar 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP6V1E1 c.634C>T (p.Arg212Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249188 control chromosomes (gnomAD). c.634C>T has been reported in the literature in the homozygous state in at least four individuals (two sets of siblings) affected with ATP6V1E1-Related Cutis Laxa from two different families wherein the variant segregated with the disease phenotype (Alazami_2016, Van Damme_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27023906, 28065471). ClinVar contains an entry for this variant (Variation ID: 417760). Based on the evidence outlined above, the variant was classified as pathogenic. -

RASopathy

Pathogenic:1

Mar 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RIT1 c.634C>T (p.Arg212Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251418 control chromosomes. The observed variant frequency is approximately 5.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in RIT1 causing Noonan Syndrome And Related Conditions phenotype (1.3e-05), strongly suggesting that the variant is benign. c.634C>T has not been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions with clear evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

4.2

H;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.4

D;D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.93

MutPred

0.85

Loss of methylation at R212 (P = 0.0162);.;.;

MVP

0.48

MPC

0.78

ClinPred

1.0

GERP RS

3.7

Varity_R

0.92

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over