Submissions for variant NM_002907.4(RECQL):c.1483G>C (p.Asp495His)

gnomAD frequency: 0.00353  dbSNP: rs6499

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000611851	SCV000714694	likely benign	not specified	2018-01-02	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.
Mendelics	RCV000709203	SCV000838632	likely benign	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV000967767	SCV001115185	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003762812	SCV001158026	likely benign	RECON progeroid syndrome	2023-10-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000611851	SCV002046722	benign	not specified	2021-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000709203	SCV002702571	benign	Hereditary cancer-predisposing syndrome	2020-07-02	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.
CeGaT Center for Human Genetics Tuebingen	RCV000967767	SCV004134525	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	RECQL: BS2
PreventionGenetics, part of Exact Sciences	RCV003935642	SCV004756607	benign	RECQL-related condition	2019-05-29	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000967767	SCV001553365	likely benign	not provided		no assertion criteria provided	clinical testing	The RECQL p.Asp495His variant was identified in 4 of 854 proband chromosomes (frequency: 0.00468) from individuals with breast and ovarian cancer (Nguyen-Dumont_2018_PMID:29351780). The variant was also identified in dbSNP (ID: rs6499), LOVD 3.0 and ClinVar (classified as likely benign by GeneDx and Mendelics for Hereditary cancer-predisposing syndrome). The variant was identified in control databases in 1075 of 281672 chromosomes (5 homozygous) at a frequency of 0.003816 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: Ashkenazi Jewish in 126 of 10312 chromosomes (freq: 0.01222), Other in 40 of 7174 chromosomes (freq: 0.005576), European (non-Finnish) in 639 of 128500 chromosomes (freq: 0.004973), Latino in 167 of 35252 chromosomes (freq: 0.004737), European (Finnish) in 66 of 25074 chromosomes (freq: 0.002632), African in 36 of 24884 chromosomes (freq: 0.001447) and South Asian in 1 of 30546 chromosomes (freq: 0.000033), but was not observed in the East Asian population. The p.Asp495 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.