rs398124484
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138694.4(PKHD1):c.3761_3762delCCinsG(p.Ala1254GlyfsTer49) variant causes a frameshift, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. AP1254G?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_138694.4 frameshift, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PKHD1 | ENST00000371117.8 | c.3761_3762delCCinsG | p.Ala1254GlyfsTer49 | frameshift_variant, synonymous_variant | Exon 32 of 67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
| PKHD1 | ENST00000340994.4 | c.3761_3762delCCinsG | p.Ala1254GlyfsTer49 | frameshift_variant, synonymous_variant | Exon 32 of 61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:7Other:1
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. -
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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. -
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188746). This variant is also known as c.3761_3762delinsG (p.Ala1254Glyfs*49). 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 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). -
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. -
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. -
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. -
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
PM3_very_strong, PVS1 -
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) -
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Polycystic kidney disease 4 Pathogenic:2
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PKHD1-related disorder Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at