rs1555763603

Positions:

• chr19-35849640-TCCGGGGTG-TAA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_Very_Strong

The NM_004646.4(NPHS1):​c.614_621delinsTT​(p.Thr205_Arg207delinsIle) variant causes a protein altering change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS1 NM_004646.4 protein_altering
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.97

Genes affected

NPHS1 (HGNC:7908): (NPHS1 adhesion molecule, nephrin) This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a disulfide_bond (size 57) in uniprot entity NPHN_HUMAN there are 16 pathogenic changes around while only 6 benign (73%) in NM_004646.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004646.4.
• PP5: Variant 19-35849641-CCGGGGTG-AA is Pathogenic according to our data. Variant chr19-35849641-CCGGGGTG-AA is described in ClinVar as [Pathogenic]. Clinvar id is 56518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.614_621delinsTT	p.Thr205_Arg207delinsIle	protein_altering_variant	6/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.614_621delinsTT	p.Thr205_Arg207delinsIle	protein_altering_variant	6/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.614_621delinsTT	p.Thr205_Arg207delinsIle	protein_altering_variant	6/28	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 11, 2018	Variant summary: NPHS1 c.614_621delinsTT (p.Thr205_Arg207delinsIle) results in an in-frame deletion-insertion that is predicted to delete 3 amino acids from the protein (i.e. Thr-Pro-Arg) and also cause the insertion of one amino acid (i.e. an Ile). The variant was absent in 246058 control chromosomes. c.614_621delinsTT has been reported in the literature in multiple individuals affected with Nephrotic Syndrome Type 1, in several cases in a homozygous form (Lenkkeri 1999, Hinkes 2007, Machuca 2010, Buscher 2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 11, 2023	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2023	This variant, c.614_621delinsTT, is a complex sequence change that results in the deletion of 3 and insertion of 1 amino acid(s) in the NPHS1 protein (p.Thr205_Arg207delinsIle). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individuals with nephrotic syndrome (PMID: 9915943, 33980730, 35278126). This variant disrupts a region of the NPHS1 protein in which other variant(s) (p.Pro206Thr) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2017	- -

Nephrotic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

May 10, 2019

This individual is heterozygous for the c.614_621delinsTT variant in the NPHS1 gene, which results in the loss of 3 amino acid residues and insertion of isoleucine, p.(Thr205_Arg207delinsIle). This variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). The p.Thr205_Arg207delinsIle (c.614_621delinsTT) variant has been described previously in patients with congenital nephrotic syndrome (CNS) in homozygous state (Lenkkeri et al 1999 Am J Hum Genet 64: 51-61; Koziell et al 2002 Hum Mol Genet 11: 379-388 - see comment for nomenclature), as well as compound heterzygous with another NPHS1 variant in a CNS patient who developed end stage renal disease (Schoeb et al 2010 Nephrol Dial Transplant 25: 2970-2976). This variant is considered to be likely pathogenic according to the ACMG guidelines (Evidence used: PM2, PM3, PM4). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555763603; hg19: chr19-36340543;