NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr) AND PKHD1-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 13, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003418109.4

Allele description [Variation Report for NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr)]

NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr)

Gene:

PKHD1:PKHD1 ciliary IPT domain containing fibrocystin/polyductin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p12.3

Genomic location:

Preferred name:

NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr)

HGVS:

NC_000006.12:g.51748086A>G
NG_008753.1:g.344540T>C
NM_138694.4:c.9530T>CMANE SELECT
NM_170724.3:c.9530T>C
NP_619639.3:p.Ile3177Thr
NP_733842.2:p.Ile3177Thr
NC_000006.11:g.51612884A>G
NM_138694.3:c.9530T>C
c.9530T>C (p.Ile3177Thr)

Protein change:

I3177T

Links:

dbSNP: rs200511261

NCBI 1000 Genomes Browser:

rs200511261

Molecular consequence:

NM_138694.4:c.9530T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170724.3:c.9530T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PKHD1-related disorder
Synonyms:: PKHD1-related condition
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004115871	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004115871

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 13, 2023)

germline

clinical testing

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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004115871.1

#	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.9530T>C variant is predicted to result in the amino acid substitution p.Ile3177Thr. This variant has been reported in several patients with polycystic kidney disease. In the majority of patients, it was detected in combination with the PKHD1 variant c.2414C>T (p.Pro805Leu) (Rossetti et al. 2003. PubMed ID: 12846734; Shuster et al. 2019. PubMed ID: 30650191; Bergmann et al. 2004. PubMed ID: 15108281; Denamur et al. 2010. PubMed ID: 19940839; PreventionGenetics). In at least four of these patients familial testing confirmed these variants were inherited as a haplotype (in cis) on the same allele (c.[2414C>T;9530T>C] p.[Pro805Leu;Ile3177Thr]), and this haplotype was in trans with a second PKHD1 variant allele (Rossetti et al. 2003. PubMed ID: 12846734 ; Shuster. 2019. PubMed ID: 30650191; Bergmann et al. 2004. PubMed ID: 15108281). However, the c.9530T>C (p.Ile3177Thr) variant has also been reported in individuals with polycystic kidney disease without p.Pro805Leu (Rossetti et al. 2003. PubMed ID: 12846734; PreventionGenetics). In one case, it was shown to be in trans with the suspected pathogenic variant c.2269A>C (p.Ile757Leu) (Rossetti et al. 2003. PubMed ID: 12846734). The c.9530T>C (p.Ile3177Thr) variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51612884-A-G). In conclusion, the haplotype c.[2414C>T;9530T>C] p.[Pro805Leu;Ile3177Thr] is considered to be pathogenic; however, the contribution of each variant is unknown. Although we suspect the c.9530T>C (p.Ile3177Thr) variant may be pathogenic, at this time the clinical significance of this variant is uncertain.

#	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: Sep 29, 2024

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