Submissions for variant NM_003640.5(ELP1):c.641del (p.Pro214fs)

dbSNP: rs759412460

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668489	SCV000793102	likely pathogenic	Familial dysautonomia	2017-07-27	criteria provided, single submitter	clinical testing
GeneID Lab - Advanced Molecular Diagnostics	RCV000668489	SCV000807810	likely pathogenic	Familial dysautonomia	2018-03-10	criteria provided, single submitter	clinical testing	This variant deletes one nucleotide resulting in an amino acid alteration, replacing a proline (P) with a glutamine (Q) at codon 214 creating a premature stop signal in the new reading frame noted as p.P214Qfs*39. The substitution is predicted to result in a non-functional ELP1 protein, either through protein truncation or nonsense-mediated mRNA decay. This mutation is considered a non-tolerated amino acid change based on in silico prediction algorithms (disease causing), and it has not been reported in the Clinical Variant Database (NCBI National Library of Medicine, NIH) but it has been described in 7 alleles out of 119208, the majority (6) belonging to heterozygous carries of Latino origin. Based on these findings and the limited literature regarding this substitution we consider it as a likely pathogenic variant.
Invitae	RCV000808850	SCV000948974	pathogenic	not provided	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro214Glnfs*39) in the ELP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ELP1 are known to be pathogenic (PMID: 18303054, 24173031). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ELP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 553108). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000668489	SCV001752551	likely pathogenic	Familial dysautonomia	2021-06-30	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002254707	SCV002526030	likely pathogenic	Medulloblastoma	2022-08-02	criteria provided, single submitter	clinical testing	The ELP1 c.641del (p.Pro214GlnfsTer39) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has been reported in at least four pediatric patients with the sonic hedgehog (SHH) subtype of medulloblastoma (PMID: 32296180, internal data). This variant has a maximum subpopulation frequency of 0.034% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Loss-of-function variants in ELP1 are known to be pathogenic (PMID: 18303054, 32296180). In summary, this variant meets criteria to be classified as likely pathogenic.
Ambry Genetics	RCV002462008	SCV002754796	pathogenic	Inborn genetic diseases	2019-08-29	criteria provided, single submitter	clinical testing	The c.641delC variant, located in coding exon 6 of the IKBKAP gene, results from a deletion of one nucleotide at nucleotide position 641, causing a translational frameshift with a predicted alternate stop codon (p.P214Qfs*39). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.