VCV002136416.2 - ClinVar

NM_138694.4(PKHD1):c.5236G>A (p.Gly1746Ser)

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.

(2)

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_138694.4(PKHD1):c.5236G>A (p.Gly1746Ser)

Variation ID: 2136416 Accession: VCV002136416.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.2 6: 52024574 (GRCh38) [ NCBI UCSC ] 6: 51889372 (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	Feb 8, 2023	May 12, 2024	Mar 4, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_138694.4:c.5236G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_619639.3:p.Gly1746Ser	missense
NM_170724.3:c.5236G>A	NP_733842.2:p.Gly1746Ser	missense
NC_000006.12:g.52024574C>T
NC_000006.11:g.51889372C>T
NG_008753.1:g.68052G>A
NG_084191.1:g.625C>T

... more HGVS ... less HGVS

Protein change

G1746S

Other names

Canonical SPDI

NC_000006.12:52024573: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.
LOC126859690	-	-	-	GRCh38	-	203
PKHD1		-	-	GRCh38 GRCh37	5041	5256

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.
Autosomal recessive polycystic kidney disease	Uncertain significance (1)	criteria provided, single submitter	Mar 4, 2022	RCV003037169.2
Polycystic kidney disease 4	Uncertain significance (1)	criteria provided, single submitter	-	RCV004546757.1

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 (Mar 04, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive polycystic kidney disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003439461.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (3) PubMed: 15805161‚ 17576681‚ 9536098 Comment: This sequence change affects codon 1746 of the PKHD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 1746 of the PKHD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKHD1 protein. This variant also falls at the last nucleotide of exon 32, which is part of the consensus splice site for this exon. This variant is present in population databases (rs745387993, gnomAD 0.01%). This variant has been observed in individual(s) with PKHD1-related conditions (PMID: 15805161). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Polycystic kidney disease 4 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005042786.1 First in ClinVar: May 12, 2024 Last updated: May 12, 2024	Comment: The missense variant c.5236G>A p.Gly1746Ser in the PKHD1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our … (more) The missense variant c.5236G>A p.Gly1746Ser in the PKHD1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Glycine at position 1746 is changed to a Serine changing protein sequence and it might alter its composition and physico- chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Gly1746Ser in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. (less) Clinical Features: Abnormality of the kidney (present)

Comment:

This sequence change affects codon 1746 of the PKHD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKHD1 protein. This variant also falls at the last nucleotide of exon 32, which is part of the consensus splice site for this exon. This variant is present in population databases (rs745387993, gnomAD 0.01%). This variant has been observed in individual(s) with PKHD1-related conditions (PMID: 15805161). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 missense variant c.5236G>A p.Gly1746Ser in the PKHD1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Glycine at position 1746 is changed to a Serine changing protein sequence and it might alter its composition and physico- chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Gly1746Ser in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been 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
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts.	Sharp AM	Journal of medical genetics	2005	PMID: 15805161
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_138694.4(PKHD1):c.5236G>A (p.Gly1746Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...