Submissions for variant NM_000282.4(PCCA):c.1558A>T (p.Ser520Cys)

gnomAD frequency: 0.00159  dbSNP: rs112237881

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493022	SCV000581973	uncertain significance	not provided	2022-10-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001083571	SCV001057872	likely benign	Propionic acidemia	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001083571	SCV001269314	uncertain significance	Propionic acidemia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330725	SCV004039565	uncertain significance	not specified	2023-08-16	criteria provided, single submitter	clinical testing	Variant summary: PCCA c.1558A>T (p.Ser520Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251172 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PCCA causing Propionic Acidemia (0.00037 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1558A>T in individuals affected with Propionic Acidemia and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=1) or VUS (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003972818	SCV004795188	likely benign	PCCA-related condition	2019-04-29	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).