Submissions for variant NM_006907.4(PYCR1):c.-48G>C

gnomAD frequency: 0.00013  dbSNP: rs376495113

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000341485	SCV000407444	uncertain significance	Cutis laxa	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.
GeneDx	RCV000579259	SCV000681130	uncertain significance	not provided	2017-11-28	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the PYCR1 gene. The c.-48 G>C variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 24/95182 (0.025%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico splice prediction analyses predict that this variant does not impact splicing; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. This nucleotide substitution occurs at a position that is conserved across species. Finally, the c.-48 G>C variant is located in the 5' untranslated region and no variants in the regulatory region of the PYCR1 gene have been reported in association with cutis laxa in HGMD (Stenson et al., 2014).
PreventionGenetics, part of Exact Sciences	RCV003418030	SCV004113229	uncertain significance	PYCR1-related disorder	2022-09-23	criteria provided, single submitter	clinical testing	The PYCR1 c.35-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. In an alternate transcript (NM_006907.3), this variant is found in a non-coding region (c.-48G>C). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-79894738-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.