NM_138694.4(PKHD1):c.5236G>C (p.Gly1746Arg) AND Autosomal recessive polycystic kidney disease

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 28, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000779512.6

Allele description [Variation Report for NM_138694.4(PKHD1):c.5236G>C (p.Gly1746Arg)]

NM_138694.4(PKHD1):c.5236G>C (p.Gly1746Arg)

Genes:

LOC126859690:MED14-independent group 3 enhancer GRCh37_chr6:51888848-51890047 [Gene]
PKHD1:PKHD1 ciliary IPT domain containing fibrocystin/polyductin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p12.2

Genomic location:

Preferred name:

NM_138694.4(PKHD1):c.5236G>C (p.Gly1746Arg)

HGVS:

NC_000006.12:g.52024574C>G
NG_008753.1:g.68052G>C
NM_138694.4:c.5236G>CMANE SELECT
NM_170724.3:c.5236G>C
NP_619639.3:p.Gly1746Arg
NP_733842.2:p.Gly1746Arg
NC_000006.11:g.51889372C>G
NM_138694.3:c.5236G>C

Protein change:

G1746R

Links:

dbSNP: rs745387993

NCBI 1000 Genomes Browser:

rs745387993

Molecular consequence:

NM_138694.4:c.5236G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170724.3:c.5236G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive polycystic kidney disease (ARPKD)
Synonyms:: POLYCYSTIC KIDNEY AND HEPATIC DISEASE 1; POLYCYSTIC KIDNEY DISEASE, INFANTILE, TYPE I; Polycystic kidney disease, infantile type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009889; MeSH: D017044; MedGen: C0085548; Orphanet: 731; Orphanet: 8378

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000916154	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Oct 12, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003439442	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 28, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15698423, 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000916154

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Oct 12, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV003439442

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 28, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD).

Bergmann C, Senderek J, Windelen E, Küpper F, Middeldorf I, Schneider F, Dornia C, Rudnik-Schöneborn S, Konrad M, Schmitt CP, Seeman T, Neuhaus TJ, Vester U, Kirfel J, Büttner R, Zerres K; APN (Arbeitsgemeinschaft für Pädiatrische Nephrologie)..

Kidney Int. 2005 Mar;67(3):829-48.

PubMed [citation]

PMID:: 15698423

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (4)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000916154.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The PKHD1 c.5236G>C (p.Gly1746Arg) missense variant has been reported in one study and found in a compound heterozygous state in a 4-month old individual affected with polycystic kidney disease (Bergmann et al. 2005). The p.Gly1746Arg variant was inherited from the father, while another PKHD1 missense variant was inherited from the mother. The variant was absent from 200 control individuals. Frequency information is not available from the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium and the Genome Aggregation Database. Based on the limited evidence, the p.Gly1746Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439442.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with polycystic kidney disease (PMID: 15698423). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 632490). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

ClinVar

Relating variation to medicine