Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_003361.4(UMOD):c.649T>G(p.Cys217Gly) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C217R) has been classified as Pathogenic.
UMOD (HGNC:12559): (uromodulin) The protein encoded by this gene is the most abundant protein in mammalian urine under physiological conditions. Its excretion in urine follows proteolytic cleavage of the ectodomain of its glycosyl phosphatidylinosital-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. This protein may act as a constitutive inhibitor of calcium crystallization in renal fluids. Excretion of this protein in urine may provide defense against urinary tract infections caused by uropathogenic bacteria. Defects in this gene are associated with the renal disorders medullary cystic kidney disease-2 (MCKD2), glomerulocystic kidney disease with hyperuricemia and isosthenuria (GCKDHI), and familial juvenile hyperuricemic nephropathy (FJHN). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2013]
UMOD Gene-Disease associations (from GenCC):
autosomal dominant medullary cystic kidney disease with or without hyperuricemia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
glomerulocystic kidney disease with hyperuricemia and isosthenuria
Inheritance: AD Classification: DEFINITIVE Submitted by: Laboratory for Molecular Medicine
familial juvenile hyperuricemic nephropathy type 1
Our verdict: Pathogenic. The variant received 12 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_003361.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-20348652-A-G is described in CliVar as Pathogenic. Clinvar id is 12256.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 69 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 0.99836 (below the threshold of 3.09). Trascript score misZ: 0.48416 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant medullary cystic kidney disease with or without hyperuricemia, familial juvenile hyperuricemic nephropathy type 1, glomerulocystic kidney disease with hyperuricemia and isosthenuria, autosomal dominant medullary cystic kidney disease with hyperuricemia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 16-20348652-A-C is Pathogenic according to our data. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-20348652-A-C is described in CliVar as Pathogenic. Clinvar id is 39418.Status of the report is no_assertion_criteria_provided, 0 stars.