NM_001009944.3:c.359T>C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_001009944.3(PKD1):āc.359T>Cā(p.Ile120Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001009944.3 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.359T>C | p.Ile120Thr | missense_variant, splice_region_variant | Exon 3 of 46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.359T>C | p.Ile120Thr | missense_variant, splice_region_variant | Exon 3 of 46 | 1 | NM_001009944.3 | ENSP00000262304.4 | ||
PKD1 | ENST00000423118.5 | c.359T>C | p.Ile120Thr | missense_variant, splice_region_variant | Exon 3 of 46 | 1 | ENSP00000399501.1 | |||
ENSG00000260447 | ENST00000562027.1 | n.-93A>G | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.41e-7 AC: 1AN: 1063184Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0AN XY: 545352
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Polycystic kidney disease, adult type Pathogenic:2Uncertain:1
PS4_Supporting+PM2_Supporting+PP4 -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated leucine rich repeat domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by a clinical laboratory in ClinVar, and observed in three individuals with polycystic kidney disease in the literature (PMID: 22508176, 31740684, 22367170). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
- -
Hemangioma;C0022680:Polycystic kidney disease;C0542518:Enlarged kidney Pathogenic:1
- -
not specified Uncertain:1
Variant summary: PKD1 c.359T>C (p.Ile120Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 149554 control chromosomes. c.359T>C has been reported in the literature in individuals affected with Polycystic Kidney Disease 1 and in at least one family it was reported to segregate with disease in two affected family members (e.g. Neumann_2012, Cornec-Le Gall_2013, Heyer_2016, Kim_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 23431072, 26823553, 31740684, 22367170). ClinVar contains an entry for this variant (Variation ID: 523386). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22508176, 23431072, 31740684, 22367170) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at