NM_001009944.3(PKD1):c.971G>T (p.Arg324Leu) AND Polycystic kidney dysplasia

Clinical significance:Benign

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:
RCV001292035.1

Allele description [Variation Report for NM_001009944.3(PKD1):c.971G>T (p.Arg324Leu)]

NM_001009944.3(PKD1):c.971G>T (p.Arg324Leu)

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.971G>T (p.Arg324Leu)
HGVS:
  • NC_000016.10:g.2118021C>A
  • NG_008617.1:g.22878G>T
  • NM_000296.4:c.971G>T
  • NM_001009944.3:c.971G>TMANE SELECT
  • NP_000287.4:p.Arg324Leu
  • NP_001009944.3:p.Arg324Leu
  • NC_000016.9:g.2168022C>A
  • NM_000296.3:c.971G>T
  • NM_001009944.2:c.971G>T
  • P98161:p.Arg324Leu
Protein change:
R324L; ARG324LEU
Links:
UniProtKB: P98161#VAR_010085; OMIM: 601313.0011; dbSNP: rs199476099
NCBI 1000 Genomes Browser:
rs199476099
Molecular consequence:
  • NM_000296.4:c.971G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001009944.3:c.971G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Polycystic kidney dysplasia
Synonyms:
Polycystic kidney disease
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
SCV001480652Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedBenignunknownclinical 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), SCV001480652.1

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

Description

The PKD1 p.Arg324Leu variant was identified in 6 of 720 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Thomas 1999, Hoefele 2011, Rossetti 2007). The variant was also identified in dbSNP (ID: rs199476099) as “With Pathogenic allele”, Clinvitae (classified as pathogenic by ClinVar), ClinVar (classified as pathogenic by OMIM), MutDB, ADPKD Mutation Database (classified as likely neutral), and PKD1-LOVD 3.0 (probably does not affect function). This variant was identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), the NHLBI GO Exome Sequencing Project in 17 of 7568 European American and in 1 of 3614 African American alleles, the genome Aggregation Database (beta, October 19th 2016) in 501 (1 homozygous) of 192856 chromosomes (freq. 0.003), the Exome Aggregation Consortium database (August 8th 2016) in 157 (1 homozygous) of 24970 chromosomes (freq. 0.006) in the following populations: European in 139 of 11896 chromosomes (freq. 0.01), Finnish in 9 of 402 chromosomes (freq. 0.02), Latino in 6 of 1292 chromosomes (freq. 0.004), African in 2 of 1452 chromosomes (freq. 0.001), Other in 1 of 204 chromosomes (freq. 0.005), increasing the likelihood this could be a low frequency benign variant. The p.Arg324 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 addition, the variant was identified with an unspecified co-occurring pathogenic variant increasing the likelihood that the p.Arg324Leu variant does not have clinical significance (Rossetti 2007). It was also identified in one individual from our lab in homozygous form, and with a co-occurring PKD2 pathogenic variant (c.1662G>A, p.Trp554X) increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign.

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

Last Updated: Nov 20, 2021

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