NM_138694.4(PKHD1):c.10181G>A (p.Cys3394Tyr) AND Autosomal recessive polycystic kidney disease

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 14, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003611571.1

Allele description

NM_138694.4(PKHD1):c.10181G>A (p.Cys3394Tyr)

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.10181G>A (p.Cys3394Tyr)

HGVS:

NC_000006.12:g.51659945C>T
NG_008753.1:g.432681G>A
NM_138694.4:c.10181G>AMANE SELECT
NP_619639.3:p.Cys3394Tyr
NC_000006.11:g.51524743C>T
NM_138694.3:c.10181G>A

Protein change:

C3394Y

Links:

dbSNP: rs1772559884

NCBI 1000 Genomes Browser:

rs1772559884

Molecular consequence:

NM_138694.4:c.10181G>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
SCV004561528	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 14, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27225849, 34536170, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004561528

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 14, 2024)

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

Citations

PubMed

Expanding the mutation spectrum in 130 probands with ARPKD: identification of 62 novel PKHD1 mutations by sanger sequencing and MLPA analysis.

Melchionda S, Palladino T, Castellana S, Giordano M, Benetti E, De Bonis P, Zelante L, Bisceglia L.

J Hum Genet. 2016 Sep;61(9):811-21. doi: 10.1038/jhg.2016.58. Epub 2016 May 26.

PubMed [citation]

PMID:: 27225849

Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes.

Ishiko S, Morisada N, Kondo A, Nagai S, Aoto Y, Okada E, Rossanti R, Sakakibara N, Nagano C, Horinouchi T, Yamamura T, Ninchoji T, Kaito H, Hamada R, Shima Y, Nakanishi K, Matsuo M, Iijima K, Nozu K.

Clin Exp Nephrol. 2022 Feb;26(2):140-153. doi: 10.1007/s10157-021-02135-3. Epub 2021 Sep 18.

PubMed [citation]

PMID:: 34536170
PMCID:: PMC8770369

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004561528.1

#	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 cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 3394 of the PKHD1 protein (p.Cys3394Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1683398). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys3394 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27225849, 34536170). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Feb 28, 2024

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