NM_138694.4(PKHD1):c.764A>G (p.Tyr255Cys) AND Autosomal recessive polycystic kidney disease

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 19, 2024
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:: RCV001855094.4

Allele description [Variation Report for NM_138694.4(PKHD1):c.764A>G (p.Tyr255Cys)]

NM_138694.4(PKHD1):c.764A>G (p.Tyr255Cys)

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.764A>G (p.Tyr255Cys)

HGVS:

NC_000006.12:g.52069471T>C
NG_008753.1:g.23155A>G
NM_138694.4:c.764A>GMANE SELECT
NM_170724.3:c.764A>G
NP_619639.3:p.Tyr255Cys
NP_733842.2:p.Tyr255Cys
NC_000006.11:g.51934269T>C
P08F94:p.Tyr255Cys

Protein change:

Y255C

Links:

UniProtKB: P08F94#VAR_066418; dbSNP: rs886042259

NCBI 1000 Genomes Browser:

rs886042259

Molecular consequence:

NM_138694.4:c.764A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_170724.3:c.764A>G - 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
SCV002262024	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19914852, 20413436, 27752906, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002262024

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 19, 2024)

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

PKHD1 sequence variations in 78 children and adults with autosomal recessive polycystic kidney disease and congenital hepatic fibrosis.

Gunay-Aygun M, Tuchman M, Font-Montgomery E, Lukose L, Edwards H, Garcia A, Ausavarat S, Ziegler SG, Piwnica-Worms K, Bryant J, Bernardini I, Fischer R, Huizing M, Guay-Woodford L, Gahl WA.

Mol Genet Metab. 2010 Feb;99(2):160-73. doi: 10.1016/j.ymgme.2009.10.010. Epub 2009 Oct 20.

PubMed [citation]

PMID:: 19914852
PMCID:: PMC2818513

Correlation of kidney function, volume and imaging findings, and PKHD1 mutations in 73 patients with autosomal recessive polycystic kidney disease.

Gunay-Aygun M, Font-Montgomery E, Lukose L, Tuchman M, Graf J, Bryant JC, Kleta R, Garcia A, Edwards H, Piwnica-Worms K, Adams D, Bernardini I, Fischer RE, Krasnewich D, Oden N, Ling A, Quezado Z, Zak C, Daryanani KT, Turkbey B, Choyke P, Guay-Woodford LM, et al.

Clin J Am Soc Nephrol. 2010 Jun;5(6):972-84. doi: 10.2215/CJN.07141009. Epub 2010 Apr 22.

PubMed [citation]

PMID:: 20413436
PMCID:: PMC2879301

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002262024.3

#	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 replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 255 of the PKHD1 protein (p.Tyr255Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of polycystic kidney disease (PMID: 19914852, 20413436, 27752906; Invitae). 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: 281899). 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) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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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