NM_001009944.3(PKD1):c.7927C>T (p.Arg2643Cys) AND Polycystic kidney disease

Clinical significance:Likely pathogenic

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001292442.1

Allele description [Variation Report for NM_001009944.3(PKD1):c.7927C>T (p.Arg2643Cys)]

NM_001009944.3(PKD1):c.7927C>T (p.Arg2643Cys)

Gene:
PKD1:polycystin 1, transient receptor potential channel interacting [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16p13.3
Genomic location:
Preferred name:
NM_001009944.3(PKD1):c.7927C>T (p.Arg2643Cys)
HGVS:
  • NC_000016.10:g.2105411G>A
  • NG_008617.1:g.35488C>T
  • NM_000296.4:c.7927C>T
  • NM_001009944.3:c.7927C>TMANE SELECT
  • NP_000287.4:p.Arg2643Cys
  • NP_001009944.3:p.Arg2643Cys
  • NC_000016.9:g.2155412G>A
  • NM_001009944.2:c.7927C>T
Protein change:
R2643C
Molecular consequence:
  • NM_000296.4:c.7927C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001009944.3:c.7927C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Polycystic kidney disease
Synonyms:
Polycystic kidney dysplasia; Enlarged polycystic kidneys; Polycystic kidneys
Identifiers:
MONDO: MONDO:0020642; MedGen: C0022680; OMIM: PS173900; Human Phenotype Ontology: HP:0000113

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001480938Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedLikely pathogenicunknownclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001480938.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The PKD1 p.Arg2643Cys variant was identified in 2 of 1564 proband chromosomes (frequency: 0.001) from individuals or families with ADPKD and was not identified in 342 control chromosomes from healthy individuals (Audrézet 2012, Garcia-Gonzalez 2007). The variant was also identified in the ADPKD Mutation database 6X as highly likely pathogenic. The variant was not identified in dbSNP, ClinVar, ClinVar, LOVD 3.0, or PKD1-LOVD. The variant was identified in control databases in 1 of 227680 chromosomes at a frequency of 0.000004 in the following population: European Non-Finnish in 1 of 106166 chromosomes (freq. 0.000009), but was not seen in African, Latino, Ashkenazi Jewish, East Asian, European Finnish and other populations (Genome Aggregation Consortium Feb 27, 2017). One study used several major criteria to judge the pathogenicity of the p.Arg2643Cys missense variant. The p.Arg2643Cys variant was confirmed to disrupt cleavage by expressing this variant in HEK293 cells and was classified as likely pathogenic (Garcia-Gonzalez 2007). The p.Arg2643Cys residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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

Last Updated: Oct 8, 2021

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