NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr) AND Polycystic kidney disease 4

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 10, 2021
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:: RCV001336942.4

Allele description [Variation Report for NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr)]

NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr)

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.9530T>C (p.Ile3177Thr)

HGVS:

NC_000006.12:g.51748086A>G
NG_008753.1:g.344540T>C
NM_138694.4:c.9530T>CMANE SELECT
NM_170724.3:c.9530T>C
NP_619639.3:p.Ile3177Thr
NP_733842.2:p.Ile3177Thr
NC_000006.11:g.51612884A>G
NM_138694.3:c.9530T>C
c.9530T>C (p.Ile3177Thr)

Protein change:

I3177T

Links:

dbSNP: rs200511261

NCBI 1000 Genomes Browser:

rs200511261

Molecular consequence:

NM_138694.4:c.9530T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170724.3:c.9530T>C - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001548523	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 10, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12846734, 15108281, 25741868
SCV003841194	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001548523

Johns Hopkins Genomics, Johns Hopkins University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 10, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003841194

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

unknown

clinical testing

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

Help

Summary from all submissions

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

A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees.

Rossetti S, Torra R, Coto E, Consugar M, Kubly V, Málaga S, Navarro M, El-Youssef M, Torres VE, Harris PC.

Kidney Int. 2003 Aug;64(2):391-403.

PubMed [citation]

PMID:: 12846734

PKHD1 mutations in families requesting prenatal diagnosis for autosomal recessive polycystic kidney disease (ARPKD).

Bergmann C, Senderek J, Schneider F, Dornia C, Küpper F, Eggermann T, Rudnik-Schöneborn S, Kirfel J, Moser M, Büttner R, Zerres K.

Hum Mutat. 2004 May;23(5):487-95.

PubMed [citation]

PMID:: 15108281

See all PubMed Citations (3)

Details of each submission

From Johns Hopkins Genomics, Johns Hopkins University, SCV001548523.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This PKHD1 variant (rs200511261) is rare (<0.1%) in a large population dataset (gnomAD: 13/250878 total alleles; 0.005%; no homozygotes) and has an entry in ClinVar. It has been observed on the opposite chromosome from other pathogenic variants in individuals affected with PKD4. Two bioinformatics tools queried predict that p.Ile3177Thr would be tolerated, while another predicts it would be damaging. The isoleucine residue at this position is partially conserved across the vertebrate species assessed; some species have a valine substitution at this position. This variant is not predicted to affect normal exon 58 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.9530T>C to be likely pathogenic.

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

From Baylor Genetics, SCV003841194.1

#	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

Last Updated: Mar 30, 2024

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