VCV002571802.4 - ClinVar

NM_138694.4(PKHD1):c.9308G>A (p.Gly3103Asp)

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.

(4)

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
Likely pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_138694.4(PKHD1):c.9308G>A (p.Gly3103Asp)

Variation ID: 2571802 Accession: VCV002571802.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.3 6: 51748308 (GRCh38) [ NCBI UCSC ] 6: 51613106 (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	Jul 17, 2023	Jun 17, 2024	Mar 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_138694.4:c.9308G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_619639.3:p.Gly3103Asp	missense
NM_170724.3:c.9308G>A	NP_733842.2:p.Gly3103Asp	missense
NC_000006.12:g.51748308C>T
NC_000006.11:g.51613106C>T
NG_008753.1:g.344318G>A

... more HGVS ... less HGVS

Protein change

G3103D

Other names

Canonical SPDI

NC_000006.12:51748307: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.
PKHD1		-	-	GRCh38 GRCh37	5054	5269

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jul 10, 2023	RCV003313511.1
PKHD1-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Apr 27, 2023	RCV003395749.4
not specified	Uncertain significance (1)	criteria provided, single submitter	Nov 15, 2023	RCV003479512.1
Polycystic kidney disease 4	Likely pathogenic (1)	criteria provided, single submitter	Mar 10, 2024	RCV004572917.1

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.
Likely pathogenic (Jul 10, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004012425.1 First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30650191) (less)
Likely pathogenic (Apr 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PKHD1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119879.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The PKHD1 c.9308G>A variant is predicted to result in the amino acid substitution p.Gly3103Asp. With a pathogenic PKHD1 frameshift variant c.353delG (p.S118Ifs35), this missense variant … (more) The PKHD1 c.9308G>A variant is predicted to result in the amino acid substitution p.Gly3103Asp. With a pathogenic PKHD1 frameshift variant c.353delG (p.S118Ifs35), this missense variant has been reported in a prenatal case with isolated bilateral hyperechogenic kidneys, but the phase was unknown (Shuster et al. 2019. PubMed ID: 30650191). Of note, we have observed this variant previously at PreventionGenetics in an affected infant in trans with a well-documented pathogenic variant c.107C>T (p.Thr36Met). The p.Gly3103Asp variant is rare in the general population (https://gnomad.broadinstitute.org/variant/6-51613106-C-T). We interpret this variant as likely pathogenic. (less)
Uncertain significance (Nov 15, 2023)	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: SCV004222713.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (1) PubMed: 30650191 Comment: Variant summary: PKHD1 c.9308G>A (p.Gly3103Asp) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein … (more) Variant summary: PKHD1 c.9308G>A (p.Gly3103Asp) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251136 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9308G>A has been reported in the literature in individuals affected with bilateral hyperchogenic kidneys (Shuster_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. 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: 30650191). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Likely pathogenic (Mar 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Polycystic kidney disease 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005056292.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30650191)

Comment:

The PKHD1 c.9308G>A variant is predicted to result in the amino acid substitution p.Gly3103Asp. With a pathogenic PKHD1 frameshift variant c.353delG (p.S118Ifs*35), this missense variant has been reported in a prenatal case with isolated bilateral hyperechogenic kidneys, but the phase was unknown (Shuster et al. 2019. PubMed ID: 30650191). Of note, we have observed this variant previously at PreventionGenetics in an affected infant in trans with a well-documented pathogenic variant c.107C>T (p.Thr36Met). The p.Gly3103Asp variant is rare in the general population (https://gnomad.broadinstitute.org/variant/6-51613106-C-T). We interpret this variant as likely pathogenic.

Comment:

Variant summary: PKHD1 c.9308G>A (p.Gly3103Asp) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251136 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9308G>A has been reported in the literature in individuals affected with bilateral hyperchogenic kidneys (Shuster_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. 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: 30650191). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. 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
Prenatal detection of isolated bilateral hyperechogenic kidneys: Etiologies and outcomes.	Shuster S	Prenatal diagnosis	2019	PMID: 30650191

Text-mined citations for this variant ...

Record last updated Jun 17, 2024

ClinVar Genomic variation as it relates to human health

NM_138694.4(PKHD1):c.9308G>A (p.Gly3103Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...