rs774738181

chr13-100262814-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000282.4(PCCA):c.802C>T(p.Arg268Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000222 in 1,438,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PCCA NM_000282.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2 B:2
• Conservation: PhyloP100: 4.37

Genes affected

PCCA (HGNC:8653): (propionyl-CoA carboxylase subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric mitochondrial enzyme Propionyl-CoA carboxylase. PCCA encodes the biotin-binding region of this enzyme. Mutations in either PCCA or PCCB (encoding the beta subunit) lead to an enzyme deficiency resulting in propionic acidemia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000282.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-100262815-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 638025.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCA	NM_000282.4	c.802C>T	p.Arg268Cys	missense_variant	10/24	ENST00000376285.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCA	ENST00000376285.6	c.802C>T	p.Arg268Cys	missense_variant	10/24	1	NM_000282.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151812 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249150 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134984

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000218 AC: 28 AN: 1286990 Hom.: 0 Cov.: 19 AF XY: 0.0000216 AC XY: 14 AN XY: 649286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.0000220

Gnomad4 OTH exome AF: 0.0000367

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151812 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74110

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Propionic acidemia Pathogenic:2 Uncertain:1 Benign:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 10, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 268 of the PCCA protein (p.Arg268Cys). 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 missense change has been observed in individual(s) with propionic acidemia (PMID: 30186825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 289402). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCCA protein function with a negative predictive value of 95%. This variant disrupts the p.Arg268 amino acid residue in PCCA. Other variant(s) that disrupt this residue have been observed in individuals with PCCA-related conditions (PMID: 30186825, 35331292), which suggests that this may be a clinically significant amino acid residue. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 21, 2018	several normal organic acids results -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 29, 2018	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 28, 2016

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 21, 2023

Variant summary: PCCA c.802C>T (p.Arg268Cys) results in a non-conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249150 control chromosomes (gnomAD). c.802C>T has been reported in the literature in individuals affected with Propionic Acidemia (Wang_2018, Liu_2023), and one was compound heterozygous with a truncating variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30186825, 36662638). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely pathogenic (n=2), uncertain significance (n=1), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.039	D;T;T
Polyphen		1.0	D;.;D
Vest4		0.97
MVP		0.99
MPC		0.73
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs774738181; hg19: chr13-100915068; COSMIC: COSV66188256;