NM_138694.4(PKHD1):c.494A>C (p.Glu165Ala) AND Autosomal recessive polycystic kidney disease

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 31, 2021
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:: RCV001303527.8

Allele description [Variation Report for NM_138694.4(PKHD1):c.494A>C (p.Glu165Ala)]

NM_138694.4(PKHD1):c.494A>C (p.Glu165Ala)

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.494A>C (p.Glu165Ala)

HGVS:

NC_000006.12:g.52073496T>G
NG_008753.1:g.19130A>C
NM_138694.4:c.494A>CMANE SELECT
NM_170724.3:c.494A>C
NP_619639.3:p.Glu165Ala
NP_733842.2:p.Glu165Ala
NC_000006.11:g.51938294T>G

Protein change:

E165A

Links:

dbSNP: rs1302500833

NCBI 1000 Genomes Browser:

rs1302500833

Molecular consequence:

NM_138694.4:c.494A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170724.3:c.494A>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

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NADH dehydrogenase subunit 1 (mitochondrion) [Tylomelania sinabartfeldi]
NADH dehydrogenase subunit 1 (mitochondrion) [Tylomelania sinabartfeldi]
gi|2704297747|gb|WXX01507.1|

Protein
Tylomelania inconspicua voucher ZMB 190709_3 NADH dehydrogenase subunit 4L (ND4L...
Tylomelania inconspicua voucher ZMB 190709_3 NADH dehydrogenase subunit 4L (ND4L) gene, complete cds; mitochondrial
gi|2704298342|gb|PP532497.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001492775	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 31, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002083404	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jun 5, 2019)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001492775

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 31, 2021)

germline

clinical testing

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

SCV002083404

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Jun 5, 2019)

germline

clinical testing

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001492775.3

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

Description

This sequence change replaces glutamic acid with alanine at codon 165 of the PKHD1 protein (p.Glu165Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. 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. 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 Natera, Inc., SCV002083404.1

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

#	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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