Submissions for variant NM_001009944.3(PKD1):c.8123C>T (p.Thr2708Met)

gnomAD frequency: 0.01193  dbSNP: rs147350387

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003891877	SCV000305786	benign	PKD1-related condition	2019-10-09	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999995	SCV000604726	benign	Polycystic kidney disease, adult type	2020-02-20	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000712656	SCV000843175	benign	not provided	2018-07-17	criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254186	SCV001430207	likely benign	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
GeneDx	RCV000712656	SCV001949023	benign	not provided	2020-02-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27499327, 24374109)
CeGaT Center for Human Genetics Tuebingen	RCV000712656	SCV002545727	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PKD1: BS1, BS2
Fulgent Genetics, Fulgent Genetics	RCV000999995	SCV002802593	likely benign	Polycystic kidney disease, adult type	2022-04-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292087	SCV001480853	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Thr2708Met variant was identified in 10 of 1016 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (classified as a polymorphism) and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2001, Rossetti 2012). This variant has been seen in one individual from our laboratory as co-occurring with a pathogenic variant increasing the likelihood it may not have clinical significance. The variant was also identified in dbSNP (ID: rs147350387) as “N/A”. The variant was identified in the 1000 Genomes Project in 20 of 5000 chromosomes (frequency: 0.004); in NHLBI GO Exome Sequencing Project in 129 of 8168 European American (frequency: 0.016) and 11 of 4082 African American (frequency: 0.0027) alleles. In the Exome Aggregation Consortium database (March 14, 2016) in 114 of 17104 chromosomes of which 1 was homozygous (frequency: 0.00666) in the following populations: 101 of 6264 European (Non-Finnish) – frequency 0.01612; 6 of 7956 South Asian- frequency 0.0007541; 3 of 490 Latinos- frequency 0.006122; 2 of 60 Finnish - frequency 0.03333; 1 of 1246 African - frequency 0.0008026 and 1 of 164 Other- frequency: 0.006098) alleles. The variant was identified in ADPKD Mutation Database classified as likely neutral. The p.Thr2708 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 benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000246229	SCV002034068	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000712656	SCV002035766	likely benign	not provided		no assertion criteria provided	clinical testing