NM_138694.4(PKHD1):c.11284C>A (p.Pro3762Thr) AND Autosomal recessive polycystic kidney disease

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 24, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000675040.6

Allele description [Variation Report for NM_138694.4(PKHD1):c.11284C>A (p.Pro3762Thr)]

NM_138694.4(PKHD1):c.11284C>A (p.Pro3762Thr)

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.11284C>A (p.Pro3762Thr)

HGVS:

NC_000006.12:g.51649111G>T
NG_008753.1:g.443515C>A
NM_138694.4:c.11284C>AMANE SELECT
NP_619639.3:p.Pro3762Thr
NC_000006.11:g.51513909G>T
NM_138694.3:c.11284C>A

Protein change:

P3762T

Links:

dbSNP: rs1229349983

NCBI 1000 Genomes Browser:

rs1229349983

Molecular consequence:

NM_138694.4:c.11284C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive polycystic kidney disease (ARPKD)
Synonyms:: POLYCYSTIC KIDNEY AND HEPATIC DISEASE 1; POLYCYSTIC KIDNEY DISEASE, INFANTILE, TYPE I; Polycystic kidney disease, infantile type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009889; MeSH: D017044; MedGen: C0085548; Orphanet: 731; Orphanet: 8378

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000800470	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jun 7, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16133180, 26673778 Citation Link,
SCV002284473	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 24, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16133180, 26673778, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000800470

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Jun 7, 2018)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002284473

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 24, 2023)

germline

clinical testing

PubMed (3)
[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	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

Analysis of missense variants in the PKHD1-gene in patients with autosomal recessive polycystic kidney disease (ARPKD).

Losekoot M, Haarloo C, Ruivenkamp C, White SJ, Breuning MH, Peters DJ.

Hum Genet. 2005 Nov;118(2):185-206. Epub 2005 Nov 15.

PubMed [citation]

PMID:: 16133180

Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies.

Schueler M, Halbritter J, Phelps IG, Braun DA, Otto EA, Porath JD, Gee HY, Shendure J, O'Roak BJ, Lawson JA, Nabhan MM, Soliman NA, Doherty D, Hildebrandt F.

J Med Genet. 2016 Mar;53(3):208-14. doi: 10.1136/jmedgenet-2015-103304. Epub 2015 Dec 16.

PubMed [citation]

PMID:: 26673778
PMCID:: PMC5057575

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000800470.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002284473.3

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

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3762 of the PKHD1 protein (p.Pro3762Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with polycystic kidney disease (PMID: 16133180, 26673778). ClinVar contains an entry for this variant (Variation ID: 558729). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as 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

Last Updated: Sep 29, 2024

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