rs188286943

Positions:

• chr16-46662452-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The ENST00000299138.12(VPS35):​c.1858G>A​(p.Asp620Asn) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS35 ENST00000299138.12 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.84

Genes affected

VPS35 (HGNC:13487): (VPS35 retromer complex component) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VPS35. . Gene score misZ 3.5321 (greater than the threshold 3.09). Trascript score misZ 4.8931 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, hereditary late onset Parkinson disease, Parkinson disease, Parkinson disease 17.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 16-46662452-C-T is Pathogenic according to our data. Variant chr16-46662452-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.1858G>A	p.Asp620Asn	missense_variant	15/17	ENST00000299138.12	NP_060676.2
VPS35	XM_011523227.4	c.1771G>A	p.Asp591Asn	missense_variant	15/17		XP_011521529.1
VPS35	XM_005256045.4	c.1657G>A	p.Asp553Asn	missense_variant	13/15		XP_005256102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.1858G>A	p.Asp620Asn	missense_variant	15/17	1	NM_018206.6	ENSP00000299138	P1
VPS35	ENST00000568784.6	c.*2528G>A		3_prime_UTR_variant, NMD_transcript_variant	15/17	1		ENSP00000456274
VPS35	ENST00000562420.1	n.496G>A		non_coding_transcript_exon_variant	3/4	2
VPS35	ENST00000647959.1	c.*1921G>A		3_prime_UTR_variant, NMD_transcript_variant	16/18			ENSP00000497702

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parkinson disease 17 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 08, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 620 of the VPS35 protein (p.Asp620Asn). Experimental studies have shown that this missense change affects VPS35 function (PMID: 23411763, 24740878). For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt VPS35 protein function. ClinVar contains an entry for this variant (Variation ID: 30196). This missense change has been observed in individual(s) with Parkinson disease (PMID: 21763482, 22154191, 22801713). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 03, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030196 / PMID: 21763482). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21763482, 21763483, 22801713, 22991136). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 21763482, 21763483, 22801713, 22991136). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2023

Published functional studies demonstrate a damaging effect, as D620N disrupts cellular autophagy and mitochondrial function (Bi et al., 2013; Ma et al., 2021); 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; This variant is associated with the following publications: (PMID: 24740878, 25416282, 26618722, 28765075, 29743203, 24557499, 22801713, 33032646, 28985717, 30842285, 33347683, 25288323, 24819384, 24152121, 26251041, 24980502, 34127073, 23125461, 22154191, 33611076, 21763482, 32707456, 23411763) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	0.0015	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.077	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.91		Gain of ubiquitination at K622 (P = 0.0898);
MVP		0.76
MPC		1.3
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.81
gMVP		0.64

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: rs188286943; hg19: chr16-46696364; COSMIC: COSV54480406; COSMIC: COSV54480406;