NM_014625.4(NPHS2):c.948del (p.Ala317fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 27, 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:: RCV000517439.7

Allele description [Variation Report for NM_014625.4(NPHS2):c.948del (p.Ala317fs)]

NM_014625.4(NPHS2):c.948del (p.Ala317fs)

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.948del (p.Ala317fs)

HGVS:

NC_000001.11:g.179551377del
NG_007535.1:g.29573del
NG_033075.1:g.190658del
NM_001297575.2:c.744del
NM_014625.4:c.948delMANE SELECT
NM_144696.6:c.3032-3135delMANE SELECT
NP_001284504.1:p.Ala249fs
NP_055440.1:p.Ala317Leufs
NP_055440.1:p.Ala317fs
NP_055440.1:p.Ala317fs
LRG_887t1:c.948del
LRG_887:g.29573del
LRG_887p1:p.Ala317fs
NC_000001.10:g.179520512del
NM_014625.2:c.948delT
NM_014625.3:c.948del
NM_014625.3:c.948delT

Protein change:

A249fs

Links:

dbSNP: rs775170915

NCBI 1000 Genomes Browser:

rs775170915

Molecular consequence:

NM_001297575.2:c.744del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014625.4:c.948del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144696.6:c.3032-3135del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000614355	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18443213, 17371932, 14978175, 15015071, 26467025
SCV001168621	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Nov 19, 2018)	germline	clinical testing	Citation Link,
SCV001577973	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14978175, 18443213, 23242530, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000614355

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Nov 1, 2016)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001168621

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Nov 19, 2018)

germline

clinical testing

Citation Link,

SCV001577973

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 27, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

NPHS2 mutation associated with recurrence of proteinuria after transplantation.

Billing H, Müller D, Ruf R, Lichtenberger A, Hildebrandt F, August C, Querfeld U, Haffner D.

Pediatr Nephrol. 2004 May;19(5):561-4. Epub 2004 Mar 10.

PubMed [citation]

PMID:: 15015071

See all PubMed Citations (7)

Details of each submission

From Athena Diagnostics, SCV000614355.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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, SCV001168621.1

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

Description

The c.948delT variant in the NPHS2 gene has been reported previously in the compound heterozygous state with a second NPHS2 variant in individuals with steroid-resistant nephrotic syndrome (Lowik et al., 2008; Kerti et al., 2013). The c.948delT variant causes a frameshift starting with codon Alanine 317, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 31 of the new reading frame, denoted p.Ala317LeufsX31. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 67 amino acids are lost and replaced with 30 incorrect amino acids. The c.948delT variant is observed in 1/24,024 (0.004%) alleles from individuals of African background and 4/276,734 (0.001%) total alleles in large population cohorts (Lek et al., 2016). We interpret c.948delT as a pathogenic variant.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577973.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Ala317Leufs*31) in the NPHS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 67 amino acid(s) of the NPHS2 protein. This variant is present in population databases (rs775170915, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with steroid-resistant nephrotic syndrome (PMID: 14978175, 18443213, 23242530). This variant is also known as p.L347X. ClinVar contains an entry for this variant (Variation ID: 188990). 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

Last Updated: Sep 29, 2024

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