NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr) AND Autosomal recessive polycystic kidney disease

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 21, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000502876.14

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:: 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000894382	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000937398	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 21, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16133180, 18503009, 19940839, 12846734, 15108281, 28492532
SCV001163019	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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

SCV000894382

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 31, 2018)

unknown

clinical testing

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

SCV000937398

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 21, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001163019

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of missense variants in the PKHD1-gene in patients with autosomal recessive polycystic kidney disease (ARPKD).

Losekoot M, Haarloo C, Ruivenkamp C, White SJ, Breuning MH, Peters DJ.

Hum Genet. 2005 Nov;118(2):185-206. Epub 2005 Nov 15.

PubMed [citation]

PMID:: 16133180

Nephrectomy in an autosomal recessive polycystic kidney disease (ARPKD) patient with rapid kidney enlargement and increased expression of EGFR.

Arbeiter A, Büscher R, Bonzel KE, Wingen AM, Vester U, Wohlschläger J, Zerres K, Nürnberger J, Bergmann C, Hoyer PF.

Nephrol Dial Transplant. 2008 Sep;23(9):3026-9. doi: 10.1093/ndt/gfn288. Epub 2008 May 23. No abstract available.

PubMed [citation]

PMID:: 18503009

See all PubMed Citations (7)

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV000894382.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000937398.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3177 of the PKHD1 protein (p.Ile3177Thr). This variant is present in population databases (rs200511261, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease on the same chromosome with another PKHD1 variant (p.Pro805Leu)(PMID: 16133180, 15108281, 18503009, 19940839). The haplotype (Pro805Leu; Ile3177Thr) has been observed on the opposite chromosome from other pathogenic variants in an individuals affected with polycystic kidney disease (PMID: 12846734, 15108281, Invitae). ClinVar contains an entry for this variant (Variation ID: 377018). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 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.

#	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 Baylor Genetics, SCV001163019.1

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

#	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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