NM_138694.4(PKHD1):c.10444C>T (p.Arg3482Cys) AND Polycystic kidney disease 4

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 9, 2024
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:: RCV001331692.5

Allele description [Variation Report for NM_138694.4(PKHD1):c.10444C>T (p.Arg3482Cys)]

NM_138694.4(PKHD1):c.10444C>T (p.Arg3482Cys)

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.10444C>T (p.Arg3482Cys)

HGVS:

NC_000006.12:g.51659682G>A
NG_008753.1:g.432944C>T
NM_138694.4:c.10444C>TMANE SELECT
NP_619639.3:p.Arg3482Cys
NC_000006.11:g.51524480G>A
NM_138694.3:c.10444C>T
P08F94:p.Arg3482Cys
c.10444C>T (p.Arg3482Cys)

Protein change:

R3482C

Links:

UniProtKB: P08F94#VAR_018591; dbSNP: rs148617572

NCBI 1000 Genomes Browser:

rs148617572

Molecular consequence:

NM_138694.4:c.10444C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV001523788	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 9, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003807434	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005042824	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	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

SCV001523788

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 9, 2024)

unknown

clinical testing

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

SCV003807434

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 22, 2022)

germline

clinical testing

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

SCV005042824

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Baylor Genetics, SCV001523788.2

#	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 Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807434.1

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

Description

ACMG classification criteria: PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005042824.1

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

Description

The missense c.10444C>Tp.Arg3482Cys variant in PKHD1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Autosomal recessive polycystic kidney disease ARPKD Quint A et al., 2016. This variant is reported with the allele frequency of 0.006% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 3482 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg3482Cys in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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 indicates that this missense variant is expected to disrupt PKHD1 protein function. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 16, 2024

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