Submissions for variant NM_000501.4(ELN):c.295_296del (p.Ala99fs)

dbSNP: rs1554669297

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627582	SCV000748582	likely pathogenic	not provided	2018-04-09	criteria provided, single submitter	clinical testing	Although the c.295_296delGC likely pathogenic variant in the ELN gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon alanine 99, changing it to a cysteine, and creating a premature stop codon at position 5 of the new reading frame, denoted p.Ala99CysfsX5. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the ELN gene have been reported in Human Gene Mutation Database in association with ELN-related disorders (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.295_296delGC variant has not been observed in large population cohorts (Lek et al., 2016).
Invitae	RCV000627823	SCV000748703	pathogenic	Supravalvar aortic stenosis	2023-02-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala99Cysfs*5) in the ELN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ELN are known to be pathogenic (PMID: 11175284). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ELN-related conditions. ClinVar contains an entry for this variant (Variation ID: 524086). For these reasons, this variant has been classified as Pathogenic.