Submissions for variant NM_004260.4(RECQL4):c.2269C>T (p.Gln757Ter)

gnomAD frequency: 0.00009  dbSNP: rs137853229

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464774	SCV000545927	pathogenic	Baller-Gerold syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln757*) in the RECQL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). This variant is present in population databases (rs137853229, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with RAPADILINO syndrome and Rothmund-Thomson syndrome (PMID: 10319867, 12734318, 18716613, 21418107, 24635570, 25120469, 27247962). ClinVar contains an entry for this variant (Variation ID: 6063). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000624444	SCV000742050	pathogenic	Inborn genetic diseases	2021-05-05	criteria provided, single submitter	clinical testing	The c.2269C>T (p.Q757*) alteration, located in exon 14 (coding exon 14) of the RECQL4 gene, consists of a C to T substitution at nucleotide position 2269. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 757. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the RECQL4 c.2269C>T alteration was observed in 0.01% (32/271122) of total alleles studied, with a frequency of 0.04% (14/35144) in the Latino subpopulation. This recurrent mutation has been reported in the homozygous state and presumed in trans with other truncating alterations in patients with RECQL4-related disorders (Siitonen, 2009; Piard, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000006435	SCV000803871	pathogenic	Rothmund-Thomson syndrome	2014-05-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763179	SCV000893778	pathogenic	Baller-Gerold syndrome; Rapadilino syndrome; Rothmund-Thomson syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004786242	SCV001821455	pathogenic	RECQL4-related disorder	2021-07-08	criteria provided, single submitter	clinical testing	Variant summary: RECQL4 c.2269C>T (p.Gln757X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00012 in 239722 control chromosomes (gnomAD). c.2269C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with RECQL4-Related Disorders (e.g. Kitao_1999, Wang_2003, Siitonen_2009). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001659686	SCV001875340	pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12734318, 10319867, 25120469, 18716613, 24635570, 21418107, 27247962, 33541411)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000984855	SCV002526020	pathogenic	Rothmund-Thomson syndrome type 2	2022-03-24	criteria provided, single submitter	clinical testing	The RECQL4 c.2269C>T (p.Gln757Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with Rothmund-Thomson syndrome and RAPADILINO syndrome (PM3_verystrong; PMID: 8737976, 10319867, 21418107, 25120469, 18716613, 18616953, 12734318, 24635570, 27247962). It has also been reported in the heterozygous state in an individual with osteosarcoma (PMID: 31604778). This variant has a maximum subpopulation frequency of 0.040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/8-145738796-G-A?dataset=gnomad_r2_1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PM3_verystrong.
Sema4, Sema4	RCV002255991	SCV002527863	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-09	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001659686	SCV005051510	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	RECQL4: PVS1, PM3:Strong, PP1:Strong, PM2
OMIM	RCV000984855	SCV000026618	pathogenic	Rothmund-Thomson syndrome type 2	2009-02-01	no assertion criteria provided	literature only