Submissions for variant NM_004260.4(RECQL4):c.2464-1G>C

gnomAD frequency: 0.00012  dbSNP: rs398124117

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174891	SCV000226284	pathogenic	not provided	2013-03-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474405	SCV000545868	pathogenic	Baller-Gerold syndrome	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 14 of the RECQL4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). This variant is present in population databases (rs398124117, gnomAD 0.3%). Disruption of this splice site has been observed in individual(s) with clinical features of Rothmund-Thomson syndrome (PMID: 12734318, 18716613, 29625052). It has also been observed to segregate with disease in related individuals. This variant is also known as g.4615G>C. ClinVar contains an entry for this variant (Variation ID: 94889). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498420	SCV002810492	pathogenic	Baller-Gerold syndrome; Rapadilino syndrome; Rothmund-Thomson syndrome type 2	2021-10-15	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325182	SCV004031113	pathogenic	Rothmund-Thomson syndrome type 2	2023-08-01	criteria provided, single submitter	clinical testing	The RECQL4 c.2464-1G>C intronic change results in a G to C substitution at the -1 position of intron 14 of the RECQL4 gene and is predicted to disrupt the acceptor splice site. This variant has been identified in the homozygous state in siblings with clinical features of Rothmund-Thomson syndrome (PMID: 12734318), and in the compound heterozygous state in an unrelated individual with clinical features of Rothmund-Thomson syndrome (PMID: 18716613). It has also been identified as heterozygous in at least one individual with leiomyosarcoma (PMID: 29625052). This variant has a maximum founder subpopulation frequency of 0.31% and a maximum non-founder subpopulation frequency of 0.0011% in gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000174891	SCV004159640	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	RECQL4: PVS1
New York Genome Center	RCV003325182	SCV005044183	pathogenic	Rothmund-Thomson syndrome type 2	2023-02-09	criteria provided, single submitter	clinical testing	The homozygous c.2464-1G>C variant identified in the RECQL4 gene is a canonical splice variant within intron 14/20, and is predicted to lead to aberrant splicing by in silico algorithm SpliceAI (delta score: 0.98 for an acceptor loss -1bp). This variant is found with low frequency in population databases (gnomADv2.1.1, gnomADv3.2.1, BRAVO-TOPMed, All of Us) with highest allele frequency in BRAVO-TOPMed (29 heterozygotes, 0 homozygotes, allele frequency: 1.10e-4), suggesting it is not a common benign variant in the populations represented in those databases. The c.2464-1G>C variant in RECQL4 is reported in ClinVar as Pathogenic (VarID:94889; 2 stars, 3 submissions, no conflicts), and has been previously reported in homozygous state in two siblings with a clinical diagnosis of Rothmund-Thomson syndrome [PMID:12734318] and in compound heterozygosity with a different canonical splice variant in an unrelated patient with a clinical diagnosis of Rothmund-Thomson syndrome [PMID:18716613]. Given its expected deleterious nature, low frequency in population databases, and presence in several affected individuals in the literature in both homozygous state and in compound heterozygosity, the homozygous c.2464-1G>C variant identified in the RECQL4 gene is reported as Pathogenic.
GeneDx	RCV000174891	SCV005443077	likely pathogenic	not provided	2024-07-03	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 32775946, 18716613, 30687805, 34869606, 35833951, 31794323, 33077847, 37331604, 38413718, 29625052, 36451132, 12734318, 31887429, 36744932)