Submissions for variant NM_002907.4(RECQL):c.1460A>C (p.Lys487Thr)

gnomAD frequency: 0.01583  dbSNP: rs6501

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000616609	SCV000714689	benign	not specified	2017-12-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000881520	SCV001024703	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003762811	SCV001471010	benign	RECON progeroid syndrome	2023-04-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002395550	SCV002699944	benign	Hereditary cancer-predisposing syndrome	2020-07-30	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000616609	SCV002773956	benign	not specified	2021-07-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000881520	SCV001549468	likely benign	not provided		no assertion criteria provided	clinical testing	The RECQL p.Lys487Thr variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs6501) and in ClinVar (classified as benign by GeneDx). The variant was also found in 1732 of 281554 chromosomes (35 homozygous) at a frequency of 0.006152 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1199 of 24862 chromosomes (freq: 0.04823), Ashkenazi Jewish in 328 of 10300 chromosomes (freq: 0.03184), Other in 26 of 7174 chromosomes (freq: 0.003624), Latino in 110 of 35228 chromosomes (freq: 0.003123), European (non-Finnish) in 64 of 128418 chromosomes (freq: 0.000498), European (Finnish) in 3 of 25068 chromosomes (freq: 0.00012) and South Asian in 2 of 30572 chromosomes (freq: 0.000065); it was not observed in the East Asian populations. 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. The p.Lys487 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we woudl lean towards a more benign role for this variant. This variant is classified as likely benign.