Submissions for variant NM_004750.5(CRLF1):c.713dup (p.Pro239fs)

dbSNP: rs768727082

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000195773	SCV000255353	pathogenic	Cold-induced sweating syndrome 1	2014-02-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515469	SCV003443140	pathogenic	not provided	2024-03-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro239Alafs*91) in the CRLF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRLF1 are known to be pathogenic (PMID: 17436252, 19012339). This variant is present in population databases (rs768727082, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive cold-induced sweating syndrome (PMID: 17436251, 24488861, 27976805). ClinVar contains an entry for this variant (Variation ID: 216913). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004020477	SCV004851635	pathogenic	Inborn genetic diseases	2022-09-26	criteria provided, single submitter	clinical testing	The c.713dupC (p.P239Afs*91) alteration, located in exon 5 (coding exon 5) of the CRLF1 gene, consists of a duplication of C at position 713, causing a translational frameshift with a predicted alternate stop codon after 91 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.713dupC allele has an overall frequency of 0.01% (26/275984) total alleles studied. The highest observed frequency was 0.05% (17/35212) of Latino alleles. This variant has been reported in the homozygous and compound heterozygous states in individuals with CRLF1-related cold-induced sweating syndrome (Dagoneau, 2007; Aljabari, 2013; González Fernández, 2013; Piras, 2014). Based on the available evidence, this alteration is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000195773	SCV005655209	pathogenic	Cold-induced sweating syndrome 1	2024-02-26	criteria provided, single submitter	clinical testing
OMIM	RCV000195773	SCV000026246	pathogenic	Cold-induced sweating syndrome 1	2007-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000195773	SCV001806773	not provided	Cold-induced sweating syndrome 1		no assertion provided	literature only	Founder variant in the Roma population (Spain)
PreventionGenetics, part of Exact Sciences	RCV004758669	SCV005348376	pathogenic	CRLF1-related disorder	2024-06-24	no assertion criteria provided	clinical testing	The CRLF1 c.713dupC variant is predicted to result in a frameshift and premature protein termination (p.Pro239Alafs*91). This variant was reported in the homozygous state in a family with Crisponi syndrome (Family 3 in Dagoneau et al. 2007. PubMed ID: 17436251), in the homozygous state in patients with cold-induced sweating syndrome (González Fernández et al. 2013. PubMed ID: 24008591; Herholz et al. 2011. PubMed ID: 21326283), and in the compound heterozygous state in a family with achalasia (Busch et al. 2017. PubMed ID: 27976805). Functional analysis showed that this variant disrupts CRLF1 secretion (Herholz et. 2011. PubMed ID: 21326283). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in CRLF1 are expected to be pathogenic. Based on this evidence, this variant is interpreted as pathogenic.