Submissions for variant NM_001009944.3(PKD1):c.7984C>T (p.Gln2662Ter)

dbSNP: rs757768731

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788913	SCV000928205	likely pathogenic	not provided	2019-02-05	criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV001281273	SCV001425198	pathogenic	Polycystic kidney disease, adult type	2020-02-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001281273	SCV003800842	likely pathogenic	Polycystic kidney disease, adult type	2023-01-10	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.7984C>T (p.Gln2662X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.4e-06 in 227002 control chromosomes (gnomAD). c.7984C>T has been reported in the literature in individuals affected with Polycystic Kidney Disease 1 (e.g. Carrera_2016, Wang_2019, Domingo-Gallego_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and on as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Lifecell International Pvt. Ltd	RCV001281273	SCV003929439	pathogenic	Polycystic kidney disease, adult type		criteria provided, single submitter	clinical testing	A Heterozygous Nonsense variant c.7984C>T in Exon 21 of the PKD1 gene that results in the amino acid substitution p.Gln2662* was identified. The observed variant has a maximum allele frequency of 0.00000% and novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 636940). This variant is reported by Wang et. al., 2019 for polycystic kidney disease. For these reasons, this variant has been classified as Pathogenic.
Eurofins-Biomnis	RCV001281273	SCV003935135	pathogenic	Polycystic kidney disease, adult type	2022-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004027374	SCV005005298	pathogenic	Inborn genetic diseases	2023-10-10	criteria provided, single submitter	clinical testing	The c.7984C>T (p.Q2662*) alteration, located in exon 21 (coding exon 21) of the PKD1 gene, consists of a C to T substitution at nucleotide position 7984. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 2662. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in the heterozygous state in multiple individuals with clinical features of PKD1-related polycystic kidney disease (Nigro, 2023; Domingo-Gallego, 2022; Wang, 2019; Carrera, 2016). Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000788913	SCV005327868	pathogenic	not provided	2024-01-23	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30369598, 33532864, 27499327, 37372416)
Fulgent Genetics, Fulgent Genetics	RCV001281273	SCV005638259	pathogenic	Polycystic kidney disease, adult type	2024-05-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004740451	SCV005363990	pathogenic	PKD1-related disorder	2024-03-26	no assertion criteria provided	clinical testing	The PKD1 c.7984C>T variant is predicted to result in premature protein termination (p.Gln2662*). This variant has been reported to be causative for autosomal dominant polycystic kidney disease (ADPKD) (see for example, Suppl. Table S3 of Carrera et al. 2016. PubMed ID: 27499327). To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in PKD1 are expected to be pathogenic. This variant is interpreted as pathogenic.