VCV001705508.5 - ClinVar

NM_004646.4(NPHS1):c.1367G>A (p.Arg456Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(2); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004646.4(NPHS1):c.1367G>A (p.Arg456Gln)

Variation ID: 1705508 Accession: VCV001705508.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.12 19: 35848114 (GRCh38) [ NCBI UCSC ] 19: 36339016 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 17, 2022	Aug 11, 2024	May 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004646.4:c.1367G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004637.1:p.Arg456Gln	missense
NC_000019.10:g.35848114C>T
NC_000019.9:g.36339016C>T
NG_013356.2:g.26174G>A
NG_051206.1:g.1480C>T
LRG_693:g.26174G>A
LRG_693t1:c.1367G>A	LRG_693p1:p.Arg456Gln

... more HGVS ... less HGVS

Protein change

R456Q

Other names

Canonical SPDI

NC_000019.10:35848113:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NPHS1		-	-	GRCh38 GRCh37	1673	1856

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Finnish congenital nephrotic syndrome	Uncertain significance (1)	criteria provided, single submitter	Sep 1, 2022	RCV002283822.1
not provided	Likely benign (1)	criteria provided, single submitter	Jan 17, 2024	RCV003101630.3
not specified	Uncertain significance (1)	criteria provided, single submitter	May 2, 2024	RCV004690282.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002572936.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). In silico tool predictions suggest no damaging … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.39; 3Cnet: 0.05). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Steroid-resistant nephrotic syndrome (present)
Likely benign (Jan 17, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003462614.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024
Uncertain significance (May 02, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005186048.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (1) PubMed: 37270787 Comment: Variant summary: NPHS1 c.1367G>A (p.Arg456Gln) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (Immunoglobulin subtype 2) of the encoded … (more) Variant summary: NPHS1 c.1367G>A (p.Arg456Gln) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (Immunoglobulin subtype 2) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 250354 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.00015 vs 0.0034), allowing no conclusion about variant significance. c.1367G>A has been reported in compound heterozygous state with a splce site variant in the literature in an individual affected with Nephrotic Syndrome, Type 1 (Jung_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 37270787). ClinVar contains an entry for this variant (Variation ID: 1705508). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.39; 3Cnet: 0.05). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

Comment:

Variant summary: NPHS1 c.1367G>A (p.Arg456Gln) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (Immunoglobulin subtype 2) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 250354 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.00015 vs 0.0034), allowing no conclusion about variant significance. c.1367G>A has been reported in compound heterozygous state with a splce site variant in the literature in an individual affected with Nephrotic Syndrome, Type 1 (Jung_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 37270787). ClinVar contains an entry for this variant (Variation ID: 1705508). Based on the evidence outlined above, the variant was classified as uncertain significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic diagnosis of kidney disease by whole exome sequencing and its clinical application.	Jung J	Clinical genetics	2023	PMID: 37270787

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004646.4(NPHS1):c.1367G>A (p.Arg456Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...