VCV000291105.19 - ClinVar

NM_153240.5(NPHP3):c.233G>T (p.Gly78Val)

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.

(9)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_153240.5(NPHP3):c.233G>T (p.Gly78Val)

Variation ID: 291105 Accession: VCV000291105.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q22.1 3: 132722123 (GRCh38) [ NCBI UCSC ] 3: 132440967 (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	Dec 6, 2016	Oct 8, 2024	Dec 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_153240.5:c.233G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_694972.3:p.Gly78Val	missense
NR_002811.2:n.374C>A		non-coding transcript variant
NR_037804.1:n.337G>T		non-coding transcript variant
NR_152743.1:n.374C>A		non-coding transcript variant
NC_000003.12:g.132722123C>A
NC_000003.11:g.132440967C>A
NG_008130.2:g.5310G>T

... more HGVS ... less HGVS

Protein change

G78V

Other names

Canonical SPDI

NC_000003.12:132722122:C:A

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.

Exome Aggregation Consortium (ExAC) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00005

The Genome Aggregation Database (gnomAD) 0.00006

Links

ClinGen: CA2622679 dbSNP: rs202142404 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.
LOC129937586	-	-	-	GRCh38	-	101
NPHP3		-	-	GRCh38 GRCh37	6	1207
NPHP3-ACAD11	-	-	-	GRCh38	-	1474
NPHP3-AS1	-	-	-	GRCh38	-	166

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.
Nephronophthisis	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 24, 2022	RCV000283485.14
Renal-hepatic-pancreatic dysplasia 1	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000343202.5
Meckel-Gruber syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000404760.5
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jun 13, 2017	RCV000726607.5
NPHP3-related Meckel-like syndrome Nephronophthisis 3 Renal-hepatic-pancreatic dysplasia 1	Uncertain significance (1)	criteria provided, single submitter	May 20, 2022	RCV002502158.1
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Dec 22, 2023	RCV004021321.1
NPHP3-related disorder	Uncertain significance (1)	no assertion criteria provided	Jun 16, 2024	RCV004739664.1

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 (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Meckel Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000441159.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Renal-Hepatic-Pancreatic Dysplasia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000441158.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Nephronophthisis Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000441157.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Sep 01, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000345803.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPHP3 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Jun 13, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000590321.3 First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019	Comment: A variant of uncertain significance has been identified in the NPHP3 gene. The G78V variant has not been published as a pathogenic variant, nor has … (more) A variant of uncertain significance has been identified in the NPHP3 gene. The G78V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G78V variant is observed in 1/8252 (0.01%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G78V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Glycine are tolerated across species. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. (less)
Uncertain significance (May 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome Nephronophthisis 3 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002812076.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Nephronophthisis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000831174.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 78 of the NPHP3 protein (p.Gly78Val). … (more) This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 78 of the NPHP3 protein (p.Gly78Val). This variant is present in population databases (rs202142404, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NPHP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 291105). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NPHP3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 22, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004990282.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The c.233G>T (p.G78V) alteration is located in exon 1 (coding exon 1) of the NPHP3 gene. This alteration results from a G to T substitution … (more) The c.233G>T (p.G78V) alteration is located in exon 1 (coding exon 1) of the NPHP3 gene. This alteration results from a G to T substitution at nucleotide position 233, causing the glycine (G) at amino acid position 78 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jun 16, 2024)	no assertion criteria provided Method: clinical testing	NPHP3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005363758.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The NPHP3 c.233G>T variant is predicted to result in the amino acid substitution p.Gly78Val. To our knowledge, this variant has not been reported in the … (more) The NPHP3 c.233G>T variant is predicted to result in the amino acid substitution p.Gly78Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

A variant of uncertain significance has been identified in the NPHP3 gene. The G78V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G78V variant is observed in 1/8252 (0.01%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G78V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Glycine are tolerated across species. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 78 of the NPHP3 protein (p.Gly78Val). This variant is present in population databases (rs202142404, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NPHP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 291105). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NPHP3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The c.233G>T (p.G78V) alteration is located in exon 1 (coding exon 1) of the NPHP3 gene. This alteration results from a G to T substitution at nucleotide position 233, causing the glycine (G) at amino acid position 78 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

The NPHP3 c.233G>T variant is predicted to result in the amino acid substitution p.Gly78Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPHP3	-	-	-	-

Text-mined citations for rs202142404 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_153240.5(NPHP3):c.233G>T (p.Gly78Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs202142404 ...