rs1028534806

Variant names:

• chr22-17592721-G-A
• rs1028534806
• NM_001696.4:c.634C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.50
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive cutis laxa type 2C

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive cutis laxa type 2, classic type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 417760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111900

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive cutis laxa type 2C Pathogenic:4

Dec 11, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	4.2	H;.;.
PhyloP100		2.5
PrimateAI	Uncertain	0.78	T
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	D
GERP RS		3.7
Varity_R		0.92
gMVP		0.90
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1028534806; hg19: chr22-18075487; COSMIC: COSV53656977; COSMIC: COSV53656977;