Submissions for variant NM_004260.4(RECQL4):c.1868G>A (p.Arg623His)

gnomAD frequency: 0.00070  dbSNP: rs201734382

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228885	SCV000288199	benign	Baller-Gerold syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764758	SCV000895896	uncertain significance	Baller-Gerold syndrome; Rapadilino syndrome; Rothmund-Thomson syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001293000	SCV001481725	uncertain significance	Rothmund-Thomson syndrome type 2	2020-12-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001354521	SCV002009932	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257440	SCV002527838	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001293000	SCV002767557	uncertain significance	Rothmund-Thomson syndrome type 2	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 11). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (165 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Arg623Cys); 7 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. Located in the ATP-binding domain (PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. Reported as a VUS and Likely Benign (ClinVar) and as a VUS in cancer patients (PMID: 28767289). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Ambry Genetics	RCV002515889	SCV003696035	uncertain significance	Inborn genetic diseases	2021-10-01	criteria provided, single submitter	clinical testing	The c.1868G>A (p.R623H) alteration is located in exon 11 (coding exon 11) of the RECQL4 gene. This alteration results from a G to A substitution at nucleotide position 1868, causing the arginine (R) at amino acid position 623 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000228885	SCV004208629	uncertain significance	Baller-Gerold syndrome	2023-05-11	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001293000	SCV005402290	uncertain significance	Rothmund-Thomson syndrome type 2	2024-04-24	criteria provided, single submitter	clinical testing	The RECQL4 c.1868G>A (p.Arg623His) missense change has a maximum subpopulation frequency of 0.1% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools are inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with RECQL4-associated conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
GeneDx	RCV001354521	SCV005874691	uncertain significance	not provided	2024-09-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with RECQL4-related disorders to our knowledge; This variant is associated with the following publications: (PMID: 32659497, 28767289, 30306255, 24728327)
ITMI	RCV000121934	SCV000086139	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354521	SCV001549162	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RECQL4 p.Arg623His variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs201734382), ClinVar (classified as a VUS by Invitae and Fulgent Genetics) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 165 of 276288 chromosomes at a frequency of 0.000597 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: European (non-Finnish) in 129 of 124888 chromosomes (freq: 0.001033), Latino in 15 of 35252 chromosomes (freq: 0.000426), Other in 3 of 7054 chromosomes (freq: 0.000425), European (Finnish) in 8 of 24974 chromosomes (freq: 0.00032), Ashkenazi Jewish in 3 of 10188 chromosomes (freq: 0.000295), African in 3 of 23878 chromosomes (freq: 0.000126), South Asian in 3 of 30568 chromosomes (freq: 0.000098), and East Asian in 1 of 19486 chromosomes (freq: 0.000051). The p.Arg623 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) 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. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004737207	SCV005350663	uncertain significance	RECQL4-related disorder	2024-03-21	no assertion criteria provided	clinical testing	The RECQL4 c.1868G>A variant is predicted to result in the amino acid substitution p.Arg623His. This variant was reported with uncertain significance in study of individuals with breast and/or ovarian cancer (Supplemental Table 8, Bonache et al. 2018. PubMed ID: 30306255) and in a study of individuals with pancreatic ductal adenocarcinoma (Shindo et al. 2017. PubMed ID: 28767289; eAppendix 1, Table 2, Hu et al. 2020. PubMed ID: 32659497). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.