rs398124484

chr6-52026047-GGG-GC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_138694.4(PKHD1):c.3761_3762delinsG(p.Ala1254GlyfsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1254A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKHD1 NM_138694.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 0.876

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-52026048-GG-C is Pathogenic according to our data. Variant chr6-52026048-GG-C is described in ClinVar as [Pathogenic]. Clinvar id is 96398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.3761_3762delinsG	p.Ala1254GlyfsTer49	frameshift_variant	32/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.3761_3762delinsG	p.Ala1254GlyfsTer49	frameshift_variant	32/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.3761_3762delinsG	p.Ala1254GlyfsTer49	frameshift_variant	32/61	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	This variant is present in population databases (rs746972457, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This sequence change creates a premature translational stop signal (p.Ala1254Glyfs*49) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease and is commonly reported in cis with a benign variant, c.3761C>G (PMID: 11898128, 12846734, 12874454, 15805161, 26721323, 31980526). This variant is also known as c.3761_3762delinsG (p.Ala1254Glyfs*49). ClinVar contains an entry for this variant (Variation ID: 188746). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_138694.3(PKHD1):c.3761_3762delCCinsG(A1254Gfs*49) is classified as pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. Sources cited for classification include the following: PMID 12846734, 12874454, 19914852, 15805161, 11898128, 15698423 and 15108277. Classification of NM_138694.3(PKHD1):c.3761_3762delCCinsG(A1254Gfs*49) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 22, 2018	The PKHD1 c.3761_3762delCCinsG (p.Ala1254GlyfsTer49) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Ala1254GlyfsTer49 variant has been reported in six studies and in a total of 18 individuals with autosomal recessive polycystic kidney disease, including in three in a homozygous state, in 14 in a compound heterozygous state, and in one in a heterozygous state (Onuchic et al. 2002; Rossetti et al. 2003; Furu et al. 2003; Bergmann et al. 2005; Sharp et al. 2005; Gunay-Aygun et al. 2010). The p.Ala1254GlyfsTer49 variant was absent from 510 control individuals and is not reported in the Exome Aggregation Consortium or Exome Sequencing Project or 1000 Genomes, in a region with good coverage, hence it is presumed to be rare. Based on the collective evidence, the p.Ala1254GlyfsTer49 variant is classified as pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 31, 2019	Variant summary: PKHD1 c.3761_3762delinsG (p.Ala1254GlyfsX49) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251498 control chromosomes. c.3761_3762delinsG has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (homozygous and compound heterozygous individuals), and authors indicate the variant is a Ashkenazi Jewish founder mutation. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 06, 2018	The p.Ala1254GlyfsX49 variant in PKHD1 has been reported in the homozygous or co mpound heterozygous state in at least 10 individuals with polycystic kidney dise ase and segregated with disease in 1 affected relative (Onuchic 2002, Furu 2003, Rossetti 2003, Sharp 2005, Quint 2016). It has also been identified in 0.7% (73 /10332) of Ashkenazi Jewish and 0.12% (43/35412) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frames hift, which alters the protein?s amino acid sequence beginning at position 1254 and leads to a premature termination codon 49 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Loss of functi on of the PKHD1 gene is an established disease mechanism in autosomal recessive polycystic kidney disease. In summary, this variant meets criteria to be classif ied as pathogenic for autosomal recessive polycystic kidney disease. ACMG/AMP Cr iteria applied: PVS1, PM3_Very Strong; PP1. -
Pathogenic, no assertion criteria provided	clinical testing	Hadassah Hebrew University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 21, 2018	A heterozygous frameshift deletion-insertion variant, NM_138694.3(PKHD1):c.3761_3762delinsG, has been identified in exon 32 of 37 of the PKHD1 gene. This deletion-insertion is predicted to create a frameshift starting at amino acid position 1254, introducing a stop codon 49 residues downstream (NP_619639.3(PKHD1):p.(Ala1254Glyfs*49)). This variant is predicted to result in loss of protein function either through truncation (including the loss of multiple domains) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.04% (126/276402 heterozygotes and 0 homozygote). The variant has previously been described as pathogenic multiple times in families with polycystic kidney disease (ClinVar, Gunay-Aygun M. et al. (2010), Rosetti S. et al. (2003), Bergmann C. et al. (2005)). Furthermore, this variant has been reported as the founder mutation in the Ashkenazi population (Quint A. et al. 2016). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 19, 2022	PM3_very_strong, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 2846734, 30609409, 20413436, 19914852, 11898128, 26721323, 15698423, 29327352, 30566001, 15805161, 12874454, 12846734, 15108277) -

Polycystic kidney disease 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -

PKHD1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2024

The PKHD1 c.3761_3762delinsG variant is predicted to result in a frameshift and premature protein termination (p.Ala1254Glyfs*49). This variant has been reported in unrelated individuals with polycystic kidney disease (Onuchic et al. 2002. PubMed ID: 11898128; Quint et al. 2015. PubMed ID: 26721323; Ceyhan-Birsoy et al. 2019. PubMed ID: 30609409). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PKHD1 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398124484; hg19: chr6-51890846;