NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 22, 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:: RCV000444254.12

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000511084	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 6, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000592907	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV000920666	Gharavi Laboratory, Columbia University	no assertion criteria provided (ACMG Guidelines, 2015)	Uncertain significance (Sep 16, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001714170	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 25, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15698423, 18503009, 12874454, 19940839, 25741868
SCV001781553	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Mar 22, 2021)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	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

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 (5)

Details of each submission

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000511084.1

#	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	not provided	not provided	not provided	not provided		not provided	0.000327	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592907.2

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

Description

The PKHD1 p.Ile3177Thr variant was identified in 10 of 974 proband chromosomes (frequency: 0.01) from individuals or families with ARPKD (Bergmann 2005, Denamur 2010, Furu 2004, Gunay-Aygun 2010, Losekoot 2005, Rosetti 2003).The variant was also identified in dbSNP (ID: rs200511261), Clinvitae database (as pathogenic by Emory genetics) RWTH AAachen University ARPKD database (as pathogenic) and PKHD1-LOVD. This variant was identified in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (freq. 0.0001) and Exome Aggregation Consortium database (March 14, 2016) in 5 of 66720 chromosomes (freq. 7.49E-05) in the European population, this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ile3177 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The case studies by Arbeiter (2008) and Denamur (2010) identify this mutation along with evolutionarily highly conserved missense change c.2414CT (p.Pro805Leu) in patients who died perinatally from ARPKD. In addition, several studies found the variant in patients with severe perinatally-fatal phenotype of ARPKD (Bergmann 2005, Furu 2004, Gunay-Aygun 2010, Rosetti 2003, Losekoot 2005). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

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

From Gharavi Laboratory, Columbia University, SCV000920666.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714170.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

PM2, PM3, PP1, PP4, PP5

#	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		1	not provided	not provided	not provided

From GeneDx, SCV001781553.1

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

Description

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 30507656, 19940839, 30595564, 15698423, 12846734, 15108281, 18503009, 30650191, 16133180, 19914852, 15108277, 12874454)

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

Last Updated: Sep 29, 2024

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