Submissions for variant NM_000282.4(PCCA):c.937C>T (p.Arg313Ter)

gnomAD frequency: 0.00003  dbSNP: rs138149179

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790683	SCV000225504	pathogenic	not provided	2013-07-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000032113	SCV000256838	pathogenic	Propionic acidemia	2012-01-01	criteria provided, single submitter	research
Counsyl	RCV000032113	SCV000792407	pathogenic	Propionic acidemia	2017-06-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000032113	SCV000919956	pathogenic	Propionic acidemia	2018-05-25	criteria provided, single submitter	clinical testing	Variant summary: PCCA c.937C>T (p.Arg313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 276992 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PCCA causing Propionic Acidemia (3.2e-05 vs 3.40e-03), allowing no conclusion about variant significance. The variant, c.937C>T, has been reported in the literature in multiple individuals affected with Propionic Acidemia (Kraus_2012, Gupta_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, with complete absence of PCCA and very low levels of PCCB in a cultured liver cells homozygous for this variant (Chapman_PCCA_HMG_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000032113	SCV000959042	pathogenic	Propionic acidemia	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg313*) in the PCCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). This variant is present in population databases (rs138149179, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with PCCA-related conditions (PMID: 9887338, 10101253, 22033733, 27227689). ClinVar contains an entry for this variant (Variation ID: 38870). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000032113	SCV002016539	pathogenic	Propionic acidemia	2019-06-04	criteria provided, single submitter	clinical testing
3billion	RCV000032113	SCV002318797	pathogenic	Propionic acidemia	2022-03-22	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27227689, 22033733). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 27227689, 22033733). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000397). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000032113	SCV002767187	pathogenic	Propionic acidemia	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with propionicacidemia (MIM#606054). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously described as pathogenic in multiple individuals with propionic acidaemia (ClinVar, PMID: 32819290, 27227689, 22033733). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000032113	SCV002818470	pathogenic	Propionic acidemia	2022-12-08	criteria provided, single submitter	clinical testing	A heterozygous single base pair deletion in exon 12 of the PCCA gene that results in a frameshift and premature truncation of the amino acids downstream to codon 313 (p.Arg313Ter) was detected. This variant has not been reported in the 1000 genomes, gnomAD and our internal databases. The in silico predictions of the variant is damaging by dbSNP and clinvar databases. The reference region is conserved across species. In summary, the variant is pathogenic.
Baylor Genetics	RCV000032113	SCV004202835	pathogenic	Propionic acidemia	2023-10-25	criteria provided, single submitter	clinical testing
GeneReviews	RCV000032113	SCV000055653	not provided	Propionic acidemia		no assertion provided	literature only
Natera, Inc.	RCV000032113	SCV002094972	pathogenic	Propionic acidemia	2020-12-31	no assertion criteria provided	clinical testing