Submissions for variant NM_000501.4(ELN):c.1621C>T (p.Arg541Ter)

dbSNP: rs137854453

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198624	SCV000250046	pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing	The c.1621C>T variant in the ELN gene has been reported previously in one newborn with severe cutis laxa, congenital pulmonary disease, supravalvular pulmonary artery stenosis, unilateral inguinal hernia and dysmorphic facial features (Graul-Neumann et al., 2008). The c.1621C>T variant alters the last (3') nucleotide of exon 24. mRNA studies using skin fibroblasts from the proband suggested that the variant abolished splicing from this exon/intron junction, resulting in in-frame skipping of this exon and expression of a protein lacking amino acids 526-540. The c.1621C>T variant was also present in this individual's unaffected father. However, expression studies using skin fibroblasts from the father showed that he had reduced expression of ELN mRNA, consistent with nonsense-mediated mRNA decay due to introduction of the R541X premature termination codon. The bases of this premature termination codon flank the intron and would only be present in an mRNA species that was spliced appropriately. The authors hypothesized that this potential difference in mRNA processing between father and son, while unexplained on a molecular/cellular level, may explain the highly variable clinical picture observed in this family (Graul- Neumann et al., 2008). The R541X variant has also been reported in association with supravalvular aortic stenosis (SVAS) in the absence of cutis laxa (reported as R570X in an alternate transcript of the ELN gene [Metcalfe et al., 2000; Li et al., 1997]). Metcalfe et al. reported R570X in one individual with sporadic, severe SVAS, peripheral pulmonary artery stenosis and bilateral inguinal hernias. Li et al. reported R570X in an individual with sporadic SVAS, and it was absent in >375 control samples. Functional studies were not performed in these cases. Other nonsense and splice site variants in the ELN gene have been reported in association with SVAS and cutis laxa. Furthermore, the c.1621C>T variants was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.1621 C>T in the ELN gene is interpreted as a disease-causing variant
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV000018207	SCV001739478	pathogenic	Supravalvar aortic stenosis	2020-02-28	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000018207	SCV004102628	pathogenic	Supravalvar aortic stenosis	2023-11-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390688	SCV004119759	pathogenic	ELN-related condition	2022-10-31	criteria provided, single submitter	clinical testing	The ELN c.1621C>T variant is predicted to result in premature protein termination (p.Arg541*). In an alternate transcript (NM_00127893.2) this variant is referred to as c.1708C>T (p.Arg570*). This variant has been reported in multiple individuals with ELN-related disease and in at least one individual it was reported to occur de novo (see for example - Li et al. 1997. PubMed ID: 9215670; Table S9 - Jin et al. 2017. PubMed ID: 28991257). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in ELN are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000018207	SCV000038486	pathogenic	Supravalvar aortic stenosis	2000-12-01	no assertion criteria provided	literature only
OMIM	RCV000018221	SCV000038500	pathogenic	Cutis laxa, autosomal dominant 1	2008-04-15	no assertion criteria provided	literature only