Submissions for variant NM_004304.5(ALK):c.871C>T (p.Arg291Cys)

gnomAD frequency: 0.00002  dbSNP: rs748854412

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000540271	SCV000648779	uncertain significance	Neuroblastoma, susceptibility to, 3	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 291 of the ALK protein (p.Arg291Cys). This variant is present in population databases (rs748854412, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 470903). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Baylor Genetics	RCV000540271	SCV004195341	uncertain significance	Neuroblastoma, susceptibility to, 3	2023-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001355742	SCV004238565	uncertain significance	not provided	2022-07-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355742	SCV001550706	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ALK p.Arg291Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs748854412), ClinVar (classified as a VUS by Invitae for neuroblastoma 3) and Cosmic (FATHMM predicted pathogenic; score=0.88). The variant was also identified in control databases in 6 of 250670 chromosomes at a frequency of 0.000024 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 1 of 18378 chromosomes (freq: 0.000054), European (non-Finnish) in 4 of 113094 chromosomes (freq: 0.000035) and South Asian in 1 of 30604 chromosomes (freq: 0.000033), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), and Other populations. The p.Arg291 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.