NM_138694.4(PKHD1):c.334G>A (p.Gly112Arg) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 11, 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:: RCV001290597.2

Allele description [Variation Report for NM_138694.4(PKHD1):c.334G>A (p.Gly112Arg)]

NM_138694.4(PKHD1):c.334G>A (p.Gly112Arg)

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.334G>A (p.Gly112Arg)

HGVS:

NC_000006.12:g.52079956C>T
NG_008753.1:g.12670G>A
NM_138694.4:c.334G>AMANE SELECT
NM_170724.3:c.334G>A
NP_619639.3:p.Gly112Arg
NP_733842.2:p.Gly112Arg
NC_000006.11:g.51944754C>T
NM_138694.3:c.334G>A

Protein change:

G112R

Links:

dbSNP: rs149841071

NCBI 1000 Genomes Browser:

rs149841071

Molecular consequence:

NM_138694.4:c.334G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170724.3:c.334G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001478686	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jan 11, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15698423, 33112055, 25646624 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001478686

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jan 11, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

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

The carboxy-terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC-activation.

Dafinger C, Mandel AM, Braun A, Göbel H, Burgmaier K, Massella L, Mastrangelo A, Dötsch J, Benzing T, Weimbs T, Schermer B, Liebau MC.

J Cell Mol Med. 2020 Dec;24(24):14633-14638. doi: 10.1111/jcmm.16014. Epub 2020 Oct 28.

PubMed [citation]

PMID:: 33112055
PMCID:: PMC7754027

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001478686.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: PKHD1 c.334G>A (p.Gly112Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 251404 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00034 vs 0.0071), allowing no conclusion about variant significance. c.334G>A has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Bergmann_2005, Eisenberger_2015, Dafinger_2020). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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

Last Updated: Jul 15, 2024

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