16-2116896-C-T

Variant names:

• chr16-2116896-C-T
• rs1555458704
• NM_001009944.3:c.1543G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_001009944.3(PKD1):​c.1543G>A​(p.Gly515Arg) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G515W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 4.17

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain C-type lectin (size 116) in uniprot entity PKD1_HUMAN there are 29 pathogenic changes around while only 4 benign (88%) in NM_001009944.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2116896-C-A is described in Lovd as [Likely_pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-2116896-C-T is Pathogenic according to our data. Variant chr16-2116896-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447972.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3, Pathogenic=1}. Variant chr16-2116896-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.1543G>A	p.Gly515Arg	missense_variant	Exon 7 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.1543G>A	p.Gly515Arg	missense_variant	Exon 7 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.27e-7 AC: 1 AN: 1375178 Hom.: 0 Cov.: 29 AF XY: 0.00000147 AC XY: 1 AN XY: 680114

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.34e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:2 Uncertain:1

Sep 23, 2022

Eurofins-Biomnis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD1 c.1543G>A; p.Gly515Arg variant (rs1555458704) is reported in the literature in an individual affected with autosomal dominant polycystic kidney disease (Chang 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 515 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Gly515Trp) has been reported in multiple individuals with autosomal dominant polycystic kidney disease, although it has not been conclusively demonstrated to cause disease (Cornec-Le Gall 2013, Kim 2019). Due to limited information, the clinical significance of the p.Gly515Arg variant is uncertain at this time. References: Chang MY et al. Novel PKD1 and PKD2 mutations in Taiwanese patients with autosomal dominant polycystic kidney disease. J Hum Genet. 2013 Nov;58(11):720-7. Cornec-Le Gall E et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013 May;24(6):1006-13. Kim H et al. Genetic Characteristics of Korean Patients with Autosomal Dominant Polycystic Kidney Disease by Targeted Exome Sequencing. Sci Rep. 2019 Nov 18;9(1):16952. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Dec 31, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.1543G>A (p.Gly515Arg) results in a non-conservative amino acid change located in the C-type lectin (CTL) or carbohydrate-recognition domain (IPR001304) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 130254 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1543G>A has been reported in the literature in unspecified individual(s) affected with Polycystic Kidney Disease 1 (Chang_2013). These report does not provide unequivocal conclusions about association of the variant with Polycystic Kidney Disease 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 23985799). ClinVar contains an entry for this variant (Variation ID: 447972). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jul 14, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 08, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as one of several PKD1 variants (phase unknown) in a patient with polycystic kidney disease in published literature (PMID: 23985799); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on splicing and protein structure/function; This variant is associated with the following publications: (PMID: 23985799) -

PKD1-related disorder Pathogenic:1

Nov 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 c.1543G>A variant is predicted to result in the amino acid substitution p.Gly515Arg. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been reported in an individual with autosomal dominant polycystic kidney disease (ADPKD) (Chang et al. 2013. PubMed ID: 23985799). In addition, we have found this variant in the heterozygous state in multiple presumably unrelated patients tested for cystic kidney disease at PreventionGenetics (internal data). Of note, a different substitution at the same codon define as c.1543G>T (p.Gly515Trp) has been reported in presumably unrelated individuals with polycystic kidney disease (Cornec-Le Gall et al. 2013. PubMed ID: 23431072, Suppl. Table 1; Domingo-Gallego et al. 2021. PubMed ID: 33532864, Suppl. Table 2; Kim et al. 2019. PubMed ID: 31740684, Suppl. Table S6C). This c.1543G>A (p.Gly515Arg) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.92		Loss of catalytic residue at W516 (P = 0.0814);Loss of catalytic residue at W516 (P = 0.0814);
MVP		0.83
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.26
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555458704; hg19: chr16-2166897;