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

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 27, 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:: RCV000169255.13

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]

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
SCV000220543	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jul 23, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 15805161, 19940839, 15108281, 12506140 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000754646	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12506140, 15108281, 15805161, 26385851, 26721323, 28492532
SCV000965800	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2007)	Likely pathogenic (Jan 1, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001163015	Baylor Genetics	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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	literature only

Citations

PubMed

Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease.

Denamur E, Delezoide AL, Alberti C, Bourillon A, Gubler MC, Bouvier R, Pascaud O, Elion J, Grandchamp B, Michel-Calemard L, Missy P, Zaccaria I, Le Nagard H, Gerard B, Loirat C; Société Française de Foetopathologie., Barbet J, Beaufrère AM, Berchel C, Bessières B, Boudjemaa S, Buenerd A, et al.

Kidney Int. 2010 Feb;77(4):350-8. doi: 10.1038/ki.2009.440. Epub 2009 Nov 25.

PubMed [citation]

PMID:: 19940839

Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1).

Bergmann C, Senderek J, Sedlacek B, Pegiazoglou I, Puglia P, Eggermann T, Rudnik-Schöneborn S, Furu L, Onuchic LF, De Baca M, Germino GG, Guay-Woodford L, Somlo S, Moser M, Büttner R, Zerres K.

J Am Soc Nephrol. 2003 Jan;14(1):76-89.

PubMed [citation]

PMID:: 12506140

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000220543.2

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

#	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 Invitae, SCV000754646.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3482 of the PKHD1 protein (p.Arg3482Cys). This variant is present in population databases (rs148617572, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease and related conditions (PMID: 12506140, 15108281, 15805161, 26385851, 26721323). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188896). 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%. 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV000965800.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163015.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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