NM_014625.4(NPHS2):c.1032del (p.Phe344fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 28, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001380043.5

Allele description [Variation Report for NM_014625.4(NPHS2):c.1032del (p.Phe344fs)]

NM_014625.4(NPHS2):c.1032del (p.Phe344fs)

Genes:

NPHS2:NPHS2 stomatin family member, podocin [Gene - OMIM - HGNC]
AXDND1:axonemal dynein light chain domain containing 1 [Gene - HGNC]

Variant type:

Deletion

Cytogenetic location:

1q25.2

Genomic location:

Preferred name:

NM_014625.4(NPHS2):c.1032del (p.Phe344fs)

HGVS:

NC_000001.11:g.179551295del
NG_007535.1:g.29657del
NG_033075.1:g.190576del
NM_001297575.2:c.828del
NM_014625.4:c.1032delMANE SELECT
NM_144696.6:c.3032-3217delMANE SELECT
NP_001284504.1:p.Phe276fs
NP_055440.1:p.Phe344Leufs
NP_055440.1:p.Phe344fs
LRG_887t1:c.1030del
LRG_887:g.29657del
LRG_887p1:p.Phe344Leufs
NC_000001.10:g.179520428del
NC_000001.10:g.179520430del
NM_014625.3:c.1030delT
NM_014625.3:c.1032del

Protein change:

F276fs

Links:

dbSNP: rs1673229720

NCBI 1000 Genomes Browser:

rs1673229720

Molecular consequence:

NM_001297575.2:c.828del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014625.4:c.1032del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144696.6:c.3032-3217del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Chain N, Chaperonin GroEL
Chain N, Chaperonin GroEL
gi|2753172369|pdb|8QXV|N

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001577972	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 4, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17371932, 23349334, 23515051, 23645318, 28780565, 29660491, 17899208, 28492532
SCV004030656	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Aug 28, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577972

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 4, 2021)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004030656

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Aug 28, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).

Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu J, Hasselbacher K, Hangan D, Ozaltin F, Zenker M, Hildebrandt F; Arbeitsgemeinschaft für Paediatrische Nephrologie Study Group..

Pediatrics. 2007 Apr;119(4):e907-19. Epub 2007 Mar 19.

PubMed [citation]

PMID:: 17371932

Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome.

McCarthy HJ, Bierzynska A, Wherlock M, Ognjanovic M, Kerecuk L, Hegde S, Feather S, Gilbert RD, Krischock L, Jones C, Sinha MD, Webb NJ, Christian M, Williams MM, Marks S, Koziell A, Welsh GI, Saleem MA; RADAR the UK SRNS Study Group..

Clin J Am Soc Nephrol. 2013 Apr;8(4):637-48. doi: 10.2215/CJN.07200712. Epub 2013 Jan 24.

PubMed [citation]

PMID:: 23349334
PMCID:: PMC3613958

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577972.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Phe344Leufs*4) in the NPHS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the NPHS2 protein. This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of steroid resistant nephrotic syndrome (PMID: 17371932, 23349334, 23515051, 23645318, 28780565). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has been reported in trans with the variant p.Arg229Gln in related affected individuals. This suggests that the combination of p.Arg229Gln and this variant may be clinically significant. This variant is also known as c.1030+1031delT (F343fsX347). ClinVar contains an entry for this variant (Variation ID: 1068472). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been shown to alter NPHS2 (podocin) protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin (PMID: 29660491). This variant disrupts a region of the NPHS2 protein in which other variant(s) (p.Val370Gly) have been observed in individuals with NPHS2-related conditions (PMID: 17899208). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV004030656.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies suggest a damaging effect due to intracellular retention and mislocalization of the resulting protein when expressed in the absence of wild-type protein (Straner et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation as the last 40 amino acids are replaced with 3 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 23645318, 23515051, 28780565, 23349334, 17371932, 29660491, 35971028)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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