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NM_138694.4(PKHD1):c.5221G>A (p.Val1741Met) AND Autosomal recessive polycystic kidney disease

Germline classification:
Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:
Nov 20, 2023
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:
RCV000004327.19

Allele description [Variation Report for NM_138694.4(PKHD1):c.5221G>A (p.Val1741Met)]

NM_138694.4(PKHD1):c.5221G>A (p.Val1741Met)

Genes:
LOC126859690:MED14-independent group 3 enhancer GRCh37_chr6:51888848-51890047 [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.5221G>A (p.Val1741Met)
HGVS:
  • NC_000006.12:g.52024589C>T
  • NG_008753.1:g.68037G>A
  • NM_138694.4:c.5221G>AMANE SELECT
  • NM_170724.3:c.5221G>A
  • NP_619639.3:p.Val1741Met
  • NP_619639.3:p.Val1741Met
  • NP_733842.2:p.Val1741Met
  • NC_000006.11:g.51889387C>T
  • NM_138694.3:c.5221G>A
  • NM_138694.4:c.5221G>A
  • P08F94:p.Val1741Met
  • p.V1741M
Protein change:
V1741M; VAL1741MET
Links:
UniProtKB: P08F94#VAR_014053; OMIM: 606702.0004; dbSNP: rs137852946
NCBI 1000 Genomes Browser:
rs137852946
Molecular consequence:
  • NM_138694.4:c.5221G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170724.3:c.5221G>A - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000024498OMIM
no assertion criteria provided
Pathogenic
(Mar 1, 2002)
germlineliterature only

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

SCV000800567Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Uncertain significance
(Aug 2, 2017)
unknownclinical testing

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

Citation Link,

SCV001163045Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenicgermlineclinical testing

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

SCV001251234Cavalleri Lab, Royal College of Surgeons in Ireland
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 5, 2020)
unknownresearch

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

SCV002231162Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Nov 20, 2023)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownyesnot providednot providednot providednot providednot providedresearch
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD).

Adeva M, El-Youssef M, Rossetti S, Kamath PS, Kubly V, Consugar MB, Milliner DM, King BF, Torres VE, Harris PC.

Medicine (Baltimore). 2006 Jan;85(1):1-21. doi: 10.1097/01.md.0000200165.90373.9a.

PubMed [citation]
PMID:
16523049

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000024498.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a man in whom the diagnosis of autosomal recessive polycystic kidney disease (PKD4; 263200) was first made at the age of 25 years on the basis of flank pain, Ward et al. (2002) found a val1741-to-met (V1741M) missense mutation in exon 32 of the PKHD1 gene, resulting from a 5221G-A nucleotide change. He had polycystic kidneys by renal imaging, but predominant changes were in the liver, which showed both congenital hepatic fibrosis and Caroli disease. He had esophageal varices, cholangitis, and splenomegaly. The patient did not have hypertension, and serum creatinine at the age of 41 years was 1.8.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000800567.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001163045.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Cavalleri Lab, Royal College of Surgeons in Ireland, SCV001251234.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)

Description

PS1, PM3, PP2, PP3, PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV002231162.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1741 of the PKHD1 protein (p.Val1741Met). This variant is present in population databases (rs137852946, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of polycystic kidney disease (PMID: 11919560, 12846734, 19914852, 30773290; 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: 4111). 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. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 26, 2024