chr1-42746713-G-GGC

Position:

• chr1-42746713-G-GGC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_022356.4(P3H1):​c.2194_2195insGC​(p.Pro732ArgfsTer17) variant causes a frameshift 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: P3H1 NM_022356.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.575

Genes affected

P3H1 (HGNC:19316): (prolyl 3-hydroxylase 1) This gene encodes an enzyme that is a member of the collagen prolyl hydroxylase family. These enzymes are localized to the endoplasmic reticulum and their activity is required for proper collagen synthesis and assembly. Mutations in this gene are associated with osteogenesis imperfecta type VIII. Three alternatively spliced transcript variants encoding different isoforms have been described. Other variants may exist, but their biological validity has not been determined. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon NOT found. This looks like a Nonstop Mediated Decay case. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-42746713-G-GGC is Pathogenic according to our data. Variant chr1-42746713-G-GGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1514343.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P3H1	NM_022356.4	c.2194_2195insGC	p.Pro732ArgfsTer17	frameshift_variant	15/15	ENST00000296388.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P3H1	ENST00000296388.10	c.2194_2195insGC	p.Pro732ArgfsTer17	frameshift_variant	15/15	1	NM_022356.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 8 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the KDEL domain (p.Lys733-p.Leu736) of the P3H1 protein that is required for the cellular retention and activity of certain types of proteins (PMID: 3545499). This variant has not been reported in the literature in individuals affected with P3H1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the P3H1 gene (p.Pro732Argfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the P3H1 protein and extend the protein by 11 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-43212384;