1-225921209-G-A

Position:

• chr1-225921209-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_013328.4(PYCR2):​c.796C>T​(p.Arg266Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,460,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PYCR2 NM_013328.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.03741
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.83

Genes affected

PYCR2 (HGNC:30262): (pyrroline-5-carboxylate reductase 2) This gene belongs to the pyrroline-5-carboxylate reductase family. The encoded mitochondrial protein catalyzes the conversion of pyrroline-5-carboxylate to proline, which is the last step in proline biosynthesis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.173 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-225921209-G-A is Pathogenic according to our data. Variant chr1-225921209-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 254247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225921209-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYCR2	NM_013328.4	c.796C>T	p.Arg266Ter	stop_gained, splice_region_variant	6/7	ENST00000343818.11	NP_037460.2
PYCR2	NM_001271681.2	c.574C>T	p.Arg192Ter	stop_gained, splice_region_variant	5/6		NP_001258610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYCR2	ENST00000343818.11	c.796C>T	p.Arg266Ter	stop_gained, splice_region_variant	6/7	1	NM_013328.4	ENSP00000342502	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249500 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460476 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726500

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 10 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozgous p.Arg192Ter variant was identified by our study in one individual with hypomyelinating leukodystrophy. This variant has been reported in 6 individuals with hypomyelinating leukodystrophy and microcephaly across 5 families (PMID: 27860360). Protein expression in skin fibroblasts from patients show absent protein. At least 5 other pathogenic loss of function have been reported in the literature and/or databases. In summary, the variant is pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27130255). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000254247 / PMID: 27130255). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 254247). This premature translational stop signal has been observed in individuals with clinical features of a hypomyelinating leukodystrophy (PMID: 27130255). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg266*) in the PYCR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the PYCR2 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2019	The R266X variant in the PYCR2 gene has been reported previously in the homozygous state in multiple unrelated patients with microcephaly, failure to thrive, global developmental delays, hypotonia, spasticity, dysmorphism, and hypomyelinating leukodystrophy (Zaki et al., 2016; Meng et al., 2017). This variant is predicted to cause loss of normal protein function through protein truncation, as 55 amino acid residues are lost. Protein expression studies performed on skin fibroblasts from patients with the homozygous R266X variant showed absence of the PYCR2 protein, while their heterozygous parents exhibited a reduction in PYCR2 protein levels (Zaki et al., 2016). The R266X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R266X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D
Vest4		0.34
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.037
dbscSNV1_RF	Benign	0.20
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: rs886037931; hg19: chr1-226108909;