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NM_004646.4(NPHS1):c.791C>A (p.Pro264Gln) AND Finnish congenital nephrotic syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Oct 19, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002471093.1

Allele description [Variation Report for NM_004646.4(NPHS1):c.791C>A (p.Pro264Gln)]

NM_004646.4(NPHS1):c.791C>A (p.Pro264Gln)

Gene:
NPHS1:NPHS1 adhesion molecule, nephrin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19q13.12
Genomic location:
Preferred name:
NM_004646.4(NPHS1):c.791C>A (p.Pro264Gln)
HGVS:
  • NC_000019.10:g.35849285G>T
  • NG_013356.2:g.25003C>A
  • NG_051206.1:g.2651G>T
  • NM_004646.4:c.791C>AMANE SELECT
  • NP_004637.1:p.Pro264Gln
  • LRG_693t1:c.791C>A
  • LRG_693:g.25003C>A
  • NC_000019.9:g.36340187G>T
  • NM_004646.3:c.791C>A
Protein change:
P264Q
Links:
dbSNP: rs34982899
NCBI 1000 Genomes Browser:
rs34982899
Molecular consequence:
  • NM_004646.4:c.791C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Finnish congenital nephrotic syndrome (NPHS1)
Synonyms:
NEPHROTIC SYNDROME, TYPE 1; Nephrosis 1, congenital, Finnish type; Congenital nephrotic syndrome 1
Identifiers:
MONDO: MONDO:0009732; MedGen: C0403399; Orphanet: 839; OMIM: 256300

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002768916Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Oct 19, 2020) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A molecular genetic analysis of childhood nephrotic syndrome in a cohort of Saudi Arabian families.

Al-Hamed MH, Al-Sabban E, Al-Mojalli H, Al-Harbi N, Faqeih E, Al Shaya H, Alhasan K, Al-Hissi S, Rajab M, Edwards N, Al-Abbad A, Al-Hassoun I, Sayer JA, Meyer BF.

J Hum Genet. 2013 Jul;58(7):480-9. doi: 10.1038/jhg.2013.27. Epub 2013 Apr 18.

PubMed [citation]
PMID:
23595123

SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract.

Evers C, Paramasivam N, Hinderhofer K, Fischer C, Granzow M, Schmidt-Bacher A, Eils R, Steinbeisser H, Schlesner M, Moog U.

Eur J Hum Genet. 2015 Dec;23(12):1627-33. doi: 10.1038/ejhg.2015.46. Epub 2015 Mar 25.

PubMed [citation]
PMID:
25804400
PMCID:
PMC4795213
See all PubMed Citations (5)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768916.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome, type 1 (MIM#256300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (42 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4152 heterozygotes, 55 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated C2-set domain (PDB). (I) 0709 - Another missense variant comparable to the one identified in this case has strong previous evidence for being benign. This alternative change (p.Pro264Arg), has been previously reported as a VUS and likely pathogenic (LOVD, PMID: 26560236), however, these reports did not acknowledge the global allele frequency and prevalence of homozygotes in the population. More recently, it has been reported as a benign polymorphism (ClinVar, PMID: 29676031, PMID: 23595123, PMID: 25804400). (SB) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been previously classified as a VUS (EGL Genetics). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024