rs141371306

chr13-100111886-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000282.4(PCCA):c.229C>T(p.Arg77Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,609,556 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R77Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PCCA NM_000282.4 missense, splice_region
• Scores: Splicing: ADA: 0.01989
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.27

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-100111887-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 631693.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 13-100111886-C-T is Pathogenic according to our data. Variant chr13-100111886-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCA	NM_000282.4	c.229C>T	p.Arg77Trp	missense_variant, splice_region_variant	3/24	ENST00000376285.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCA	ENST00000376285.6	c.229C>T	p.Arg77Trp	missense_variant, splice_region_variant	3/24	1	NM_000282.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000479

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250426 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135442

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1457580 Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9 AN XY: 725290

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151976 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74230

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

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: 0.000479

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Propionic acidemia Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2018	Variant summary: PCCA c.229C>T (p.Arg77Trp) results in a non-conservative amino acid change located in the Biotin carboxylation domain & Biotin carboxylase-like, N-terminal domain of 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 2e-05 in 245438 control chromosomes (gnomAD). c.229C>T has been reported in the literature in individuals affected with Propionic Acidemia (Chiu_2014, Perez_2010, Yang_2004, Perez-Cerda_2000). These data indicate that the variant is likely to be associated with disease. Experimental evidence reported in a publication evaluating an impact on protein function (Clavero_2002) demonstrated the variant to clearly diminish PCC activity (<10% of normal activity). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 19, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 77 of the PCCA protein (p.Arg77Trp). This variant is present in population databases (rs141371306, gnomAD 0.02%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 10780784, 15059621, 20549364, 24863100). This variant is also known as 154C>T (R52W). ClinVar contains an entry for this variant (Variation ID: 550747). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PCCA function (PMID: 12385775). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 28, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.93
MVP		0.99
MPC		0.64
ClinPred		1.0	D
GERP RS		1.9
Varity_R		0.96
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.020
dbscSNV1_RF	Benign	0.17
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: rs141371306; hg19: chr13-100764140;