Submissions for variant NM_018026.4(PACS1):c.2776+4C>T

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002806273	SCV003033712	uncertain significance	Schuurs-Hoeijmakers syndrome	2022-07-02	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with PACS1-related conditions. 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 create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change falls in intron 23 of the PACS1 gene. It does not directly change the encoded amino acid sequence of the PACS1 protein. It affects a nucleotide within the consensus splice site.
GeneDx	RCV003154261	SCV003842849	uncertain significance	not provided	2022-09-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700831	SCV005203409	uncertain significance	not specified	2024-07-18	criteria provided, single submitter	clinical testing	Variant summary: PACS1 c.2776+4C>T alters a non-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: Three predict the variant weakens a 5' donor site. Two predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251154 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2776+4C>T in individuals affected with Schuurs-Hoeijmakers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1991358). Based on the evidence outlined above, the variant was classified as uncertain significance.