Submissions for variant NM_004646.4(NPHS1):c.619del (p.Arg207fs)

dbSNP: rs778217926

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412108	SCV000485436	likely pathogenic	Finnish congenital nephrotic syndrome	2015-12-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412108	SCV000917906	pathogenic	Finnish congenital nephrotic syndrome	2021-02-19	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.619delC (p.Arg207GlyfsX28) 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 8e-06 in 251218 control chromosomes. c.619delC has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1 (Machuca_2010, Wong_2013, Berody_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380445	SCV001578526	pathogenic	not provided	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg207Glyfs*28) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). This variant is present in population databases (rs778217926, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with NPHS1-related conditions (PMID: 20507940, 29474669). ClinVar contains an entry for this variant (Variation ID: 370188). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000412108	SCV002800490	pathogenic	Finnish congenital nephrotic syndrome	2024-03-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000412108	SCV004191388	pathogenic	Finnish congenital nephrotic syndrome	2024-03-09	criteria provided, single submitter	clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328090	SCV001449382	likely pathogenic	Nephrotic syndrome	2018-06-28	no assertion criteria provided	clinical testing	This individual is heterozygous for the c.619del variant in the NPHS1 gene. This frameshifting variant is predicted to create a premature stop codon p.(Arg207Glyfs*28) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.008% (2 out of 246,004 alleles). To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. However, other truncating variants downstream of this amino acid have been described in the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/?term=NPHS1%5Bgene%5D). This variant is considered to be likely pathogenic according to the ACMG guidelines.
Natera, Inc.	RCV000412108	SCV002087103	pathogenic	Finnish congenital nephrotic syndrome	2020-09-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003392225	SCV004120075	pathogenic	NPHS1-related disorder	2024-05-11	no assertion criteria provided	clinical testing	The NPHS1 c.619delC variant is predicted to result in a frameshift and premature protein termination (p.Arg207Glyfs*28). This variant was reported in individuals with nephrotic syndrome (Machuca et al 2010. PubMed ID: 20507940; Bérody et al 2019. PubMed ID: 29474669; Wong et al 2013. PubMed ID: 23949594). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in NPHS1 are expected to be pathogenic. This variant is interpreted as pathogenic.