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NM_138694.4(PKHD1):c.2179A>G (p.Asn727Asp) AND Polycystic kidney disease 4

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 31, 2022
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:
RCV002471850.1

Allele description [Variation Report for NM_138694.4(PKHD1):c.2179A>G (p.Asn727Asp)]

NM_138694.4(PKHD1):c.2179A>G (p.Asn727Asp)

Gene:
PKHD1:PKHD1 ciliary IPT domain containing fibrocystin/polyductin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p12.2
Genomic location:
Preferred name:
NM_138694.4(PKHD1):c.2179A>G (p.Asn727Asp)
HGVS:
  • NC_000006.12:g.52050257T>C
  • NG_008753.1:g.42369A>G
  • NM_138694.4:c.2179A>GMANE SELECT
  • NM_170724.3:c.2179A>G
  • NP_619639.3:p.Asn727Asp
  • NP_733842.2:p.Asn727Asp
  • NC_000006.11:g.51915055T>C
  • NM_138694.3:c.2179A>G
Protein change:
N727D
Molecular consequence:
  • NM_138694.4:c.2179A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170724.3:c.2179A>G - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002766844Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 31, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766844.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant intrafamilial variation of severity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. This alternative change (p.(Asn727Ser)), has been reported several times as a VUS (ClinVar), but also as possibly pathogenic in a compound heterozygous individual with severe polycystic kidney disease (LOVD, PMID: 16133180). Another missense variant of stronger Grantham change (p.(Asn727Lys)) has also been described as likely benign (LOVD). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (p.(Ile2331Lys)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 30, 2024