rs875989838

Positions:

• chr3-190120434-CG-C
• chr3-190120434-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018192.4(P3H2):​c.297delC​(p.Gly100fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000556 in 1,258,488 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: P3H2 NM_018192.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.180

Genes affected

P3H2 (HGNC:19317): (prolyl 3-hydroxylase 2) This gene encodes a member of the prolyl 3-hydroxylase subfamily of 2-oxo-glutarate-dependent dioxygenases. These enzymes play a critical role in collagen chain assembly, stability and cross-linking by catalyzing post-translational 3-hydroxylation of proline residues. Mutations in this gene are associated with nonsyndromic severe myopia with cataract and vitreoretinal degeneration, and downregulation of this gene may play a role in breast cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-190120434-CG-C is Pathogenic according to our data. Variant chr3-190120434-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 225632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P3H2	NM_018192.4	c.297delC	p.Gly100fs	frameshift_variant	1/15	ENST00000319332.10	NP_060662.2
P3H2	NM_001134418.2	c.-64+1768delC		intron_variant			NP_001127890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P3H2	ENST00000319332.10	c.297delC	p.Gly100fs	frameshift_variant	1/15	1	NM_018192.4	ENSP00000316881.5
P3H2	ENST00000427335.6	c.-64+1768delC		intron_variant		1		ENSP00000408947.2
P3H2	ENST00000426003.1	c.-64+1102delC		intron_variant		4		ENSP00000394326.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000556 AC: 7 AN: 1258488 Hom.: 0 Cov.: 32 AF XY: 0.00000809 AC XY: 5 AN XY: 617744

Gnomad4 AFR exome AF: 0.0000399

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000522

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000157

Gnomad4 FIN exome AF: 0.0000347

Gnomad4 NFE exome AF: 0.00000294

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopia, high, with cataract and vitreoretinal degeneration Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change creates a premature translational stop signal (p.Gly100Alafs*104) in the P3H2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in P3H2 are known to be pathogenic (PMID: 24172257, 25469533). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of myopia with cataract and vitreoretinal degeneration (PMID: 25469533). It has also been observed to segregate with disease in related individuals. This variant is also known as LEPREL1 c.292delC. ClinVar contains an entry for this variant (Variation ID: 225632). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs875989838; hg19: chr3-189838223;