NM_138694.4(PKHD1):c.9719G>T (p.Arg3240Leu) AND Polycystic kidney disease 4

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Oct 4, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003474810.2

Allele description [Variation Report for NM_138694.4(PKHD1):c.9719G>T (p.Arg3240Leu)]

NM_138694.4(PKHD1):c.9719G>T (p.Arg3240Leu)

Gene:

PKHD1:PKHD1 ciliary IPT domain containing fibrocystin/polyductin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p12.3

Genomic location:

Preferred name:

NM_138694.4(PKHD1):c.9719G>T (p.Arg3240Leu)

HGVS:

NC_000006.12:g.51747897C>A
NG_008753.1:g.344729G>T
NM_138694.4:c.9719G>TMANE SELECT
NM_170724.3:c.9719G>T
NP_619639.3:p.Arg3240Leu
NP_619639.3:p.Arg3240Leu
NP_733842.2:p.Arg3240Leu
NC_000006.11:g.51612695C>A
NM_138694.3:c.9719G>T

Protein change:

R3240L

Links:

dbSNP: rs146649803

NCBI 1000 Genomes Browser:

rs146649803

Molecular consequence:

NM_138694.4:c.9719G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170724.3:c.9719G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Polycystic kidney disease 4 (PKD4)
Synonyms:: POLYCYSTIC KIDNEY DISEASE 4 WITH OR WITHOUT POLYCYSTIC LIVER DISEASE; PKD3
Identifiers:: MONDO: MONDO:0033004; MedGen: C4540575; OMIM: 263200

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004202262	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 4, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086600	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 16, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15805161, 20301501, 21945273, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004202262

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 4, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005086600

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 16, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts.

Sharp AM, Messiaen LM, Page G, Antignac C, Gubler MC, Onuchic LF, Somlo S, Germino GG, Guay-Woodford LM.

J Med Genet. 2005 Apr;42(4):336-49. No abstract available.

PubMed [citation]

PMID:: 15805161
PMCID:: PMC1736033

Autosomal Recessive Polycystic Kidney Disease – PKHD1..

Burgmaier K, Gimpel C, Schaefer F, Liebau M.

2001 Jul 19 [updated 2024 Apr 4]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301501

See all PubMed Citations (4)

Details of each submission

From Baylor Genetics, SCV004202262.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086600.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease, however there are emerging reports of heterozygous carriers of PKHD1 variants developing liver cysts and nephrocalcinosis (PMID: 21945273). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant intra-familial variability has been reported (PMID: 20301501). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg3240Gln) has been classified as likely pathogenic or pathogenic by several clinical laboratories in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and as a VUS by clinical laboratories in ClinVar, and has also been observed in a fetus with ARPKD who also had another missense variant (PMID: 15805161). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

ClinVar

Relating variation to medicine