Submissions for variant NM_000532.5(PCCB):c.183+3G>C

dbSNP: rs398123461

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281914	SCV002570638	likely pathogenic	Propionic acidemia	2022-07-30	criteria provided, single submitter	clinical testing	Variant summary: PCCB c.183+3G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.3e-06 in 235206 control chromosomes. c.183+3G>C has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Propionic Acidemia, one of whom continues to be cited by others (example, Rodriguez-Pombo_1998, cited in Perez-Cerda_2000, Stanescu_2021, Levesque_2011). 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. 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 likely pathogenic.
GeneDx	RCV000079092	SCV003805357	likely pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 9683601, 33473339)
PreventionGenetics, part of Exact Sciences	RCV003415845	SCV004112907	likely pathogenic	PCCB-related disorder	2023-03-30	criteria provided, single submitter	clinical testing	The PCCB c.183+3G>C variant is predicted to interfere with splicing. This variant was reported along with a second PCCB variant in at least two individuals with propionic acidemia (Rodriguez-Pombo et al 1998. PubMed ID: 9683601; Lévesque et al. 2011. PubMed ID: 23430860). We have also observed this variant along with a second pathogenic loss-of-function variant in PCCB in one patient with a suspected clinical diagnosis of propionic acidemia (PreventionGenetics internal data). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-135969403-G-C). Taken together, this variant is interpreted as likely pathogenic.
Baylor Genetics	RCV002281914	SCV004205183	likely pathogenic	Propionic acidemia	2023-10-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002281914	SCV004293505	likely pathogenic	Propionic acidemia	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the PCCB gene. It does not directly change the encoded amino acid sequence of the PCCB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs398123461, gnomAD 0.003%). This variant has been observed in individual(s) with propionic aciduria (PMID: 9683601, 23430860, 33473339). This variant is also known as IVS1+3G>C. ClinVar contains an entry for this variant (Variation ID: 93227). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Eurofins Ntd Llc (ga)	RCV000079092	SCV000110961	uncertain significance	not provided	2013-11-14	flagged submission	clinical testing