6-52071009-T-G

Variant names:

• chr6-52071009-T-G
• rs369925690
• NM_138694.4:c.664A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_138694.4(PKHD1):​c.664A>C​(p.Ile222Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,432,278 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I222V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.44
• Publications: 12 publications found

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124901327 (HGNC:):

ACMG classification

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

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52071009-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 406891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 6-52071009-T-G is Pathogenic according to our data. Variant chr6-52071009-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1371356.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. 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
	PKHD1	NM_138694.4	MANE Select	c.664A>C	p.Ile222Leu	missense	Exon 9 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.664A>C	p.Ile222Leu	missense	Exon 9 of 61	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.664A>C	p.Ile222Leu	missense	Exon 9 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.664A>C	p.Ile222Leu	missense	Exon 9 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432278 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 714758

African (AFR) AF: 0.00 AC: 0 AN: 32868

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1085046

Other (OTH) AF: 0.00 AC: 0 AN: 59434

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:1 Uncertain:1

May 27, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKHD1 c.664A>C (p.Ile222Leu) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant was absent in 250892 control chromosomes. c.664A>C has been observed in the compound heterozygous state in individuals affected with Polycystic Kidney And Hepatic Disease (Schueler_2016, Thomas_2020). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as likely pathogenic/pathogenic by our lab (c.664A>G, p.Ile222Val), supporting the critical relevance of codon 222 to PKHD1 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26673778, 32203225). ClinVar contains an entry for this variant (Variation ID: 1371356). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with leucine at codon 222 of the PKHD1 protein (p.Ile222Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Ile222 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11919560, 12506140, 12846734, 15698423). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided Pathogenic:1

May 16, 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 indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27225849, 20413436, 11919560, 11898128, 15698423, 32203225, 26673778, 35812281)

Polycystic kidney disease 4 Pathogenic:1

Mar 01, 2024

Baylor 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	Benign	0.24
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.069
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.088	T
Polyphen		0.77	P
Vest4		0.67
MutPred		0.54		Loss of catalytic residue at I222 (P = 0.177)
MVP		0.92
MPC		0.13
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.45
gMVP		0.78
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs369925690; hg19: chr6-51935807;