Submissions for variant NM_000214.3(JAG1):c.1720G>C (p.Val574Leu)

dbSNP: rs2067320699

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219403	SCV001391339	pathogenic	Alagille syndrome due to a JAG1 point mutation	2019-05-23	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1720 nucleotide in the JAG1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 27256232). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed to be de novo in an individual affected with Alagille syndrome (PMID: 17949281). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 574 of the JAG1 protein (p.Val574Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant also falls at the last nucleotide of exon 13 of the JAG1 coding sequence, which is part of the consensus splice site for this exon.
PreventionGenetics, part of Exact Sciences	RCV004548074	SCV004724180	likely pathogenic	JAG1-related disorder	2023-12-19	no assertion criteria provided	clinical testing	The JAG1 c.1720G>C variant is predicted to result in the amino acid substitution p.Val574Leu. This variant was reported presumably de novo in an individual with Alagille syndrome (Samejima et al. 2007. PubMed ID: 17949281). This variant has not been reported in a large population database, indicating this variant is rare. A different nucleotide substitution affecting the same amino acid (c.1720G>A, p.Val574Met) has been reported in an individual with Alagille syndrome (Gao et al. 2016. PubMed ID: 27256232). Both c.1720G>C and c.1720G>A variants affect the last nucleotide of an exon and are predicted to alter splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1). Taken together, the c.1720G>C (p.Val574Leu) variant is interpreted as likely pathogenic.