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NM_138694.4(PKHD1):c.8351A>G (p.Tyr2784Cys) AND Autosomal recessive polycystic kidney disease

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jul 6, 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:
RCV001328216.4

Allele description [Variation Report for NM_138694.4(PKHD1):c.8351A>G (p.Tyr2784Cys)]

NM_138694.4(PKHD1):c.8351A>G (p.Tyr2784Cys)

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.8351A>G (p.Tyr2784Cys)
HGVS:
  • NC_000006.12:g.51791325T>C
  • NG_008753.1:g.301301A>G
  • NM_138694.4:c.8351A>GMANE SELECT
  • NM_170724.3:c.8351A>G
  • NP_619639.3:p.Tyr2784Cys
  • NP_733842.2:p.Tyr2784Cys
  • NC_000006.11:g.51656123T>C
  • NM_138694.3:c.8351A>G
Protein change:
Y2784C
Links:
dbSNP: rs1793710520
NCBI 1000 Genomes Browser:
rs1793710520
Molecular consequence:
  • NM_138694.4:c.8351A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170724.3:c.8351A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001449400Sydney Genome Diagnostics, Children's Hospital Westmead
no assertion criteria provided
Uncertain significance
(Jul 24, 2018)
unknownclinical testing

SCV003206589Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jul 6, 2022)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Sydney Genome Diagnostics, Children's Hospital Westmead, SCV001449400.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

This individual is heterozygous for the c.8351A>G variant in the PKHD1 gene. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster suggest that this variant is likely to be pathogenic. However, this analysis alone cannot be used to confirm pathogenicity. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003206589.2

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 988201). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2784 of the PKHD1 protein (p.Tyr2784Cys).

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

Last Updated: Sep 29, 2024