16-2114843-A-T

Variant names:

• chr16-2114843-A-T
• rs1616940
• NM_001009944.3:c.2180T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_001009944.3(PKD1):​c.2180T>A​(p.Leu727Gln) 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. L727R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.42
• Publications: 11 publications found

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]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2114843-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 994718.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 16-2114843-A-T is Pathogenic according to our data. Variant chr16-2114843-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586255.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.2180T>A	p.Leu727Gln	missense	Exon 11 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.2180T>A	p.Leu727Gln	missense	Exon 11 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.2180T>A	p.Leu727Gln	missense	Exon 11 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.2180T>A	p.Leu727Gln	missense	Exon 11 of 46	ENSP00000399501.1
	PKD1	ENST00000568591.5	TSL:2	n.*508T>A		non_coding_transcript_exon	Exon 7 of 12	ENSP00000457162.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Feb 01, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 12, 2024

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the PKD1 gene demonstrated a sequence change, c.2180T>A, in exon 11 that results in an amino acid change, p.Leu727Gln. The p.Leu727Gln change affects a moderately conserved amino acid residue located in a domain of the PKD1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu727Gln substitution. This particular amino acid change has been described in the literature in individuals with cystic kidney disease; in one of those individuls, it was reported to be de novo in nature (PMID: 29801666) . Different sequence changes affecting the same amino acid residues (p.Leu727Pro, p.Leu727Arg) have been described in individuals with autosomal dominant polycystic kidney disease (PMID: 22508176, 27499327, 26150605, 21115670, 22383692, 24374109). This sequence change has not been described in population databases such as ExAC and gnomAD (dbSNP rs1616940). Collectively, this evidence indicates that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively.

Apr 29, 2024

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; This variant is associated with the following publications: (PMID: 29801666)

Polycystic kidney disease, adult type Pathogenic:1

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.39		Gain of disorder (P = 0.0613)
MVP		0.85
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.46
gMVP		0.88
Mutation Taster		=2/98	disease causing

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: rs1616940; hg19: chr16-2164844;