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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024498	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000800567	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Aug 2, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16523049, 11919560, 19914852 Citation Link,
SCV001163045	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001251234	Cavalleri Lab, Royal College of Surgeons in Ireland	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 5, 2020)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV002231162	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11919560, 12846734, 19914852, 30773290, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature 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.

#	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	not provided	not provided	not provided

From Counsyl, SCV000800567.1

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

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

From Baylor Genetics, SCV001163045.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

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

Description

PS1, PM3, PP2, PP3, PP4

#	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 Invitae, SCV002231162.4

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

#	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: Apr 20, 2024

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