Submissions for variant NM_003401.5(XRCC4):c.25del (p.His9fs)

dbSNP: rs869320677

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594218	SCV000702106	pathogenic	not provided	2016-09-28	criteria provided, single submitter	clinical testing
Invitae	RCV000594218	SCV001228277	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His9Thrfs*8) in the XRCC4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XRCC4 are known to be pathogenic (PMID: 25728776). This variant is present in population databases (rs757928483, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with short stature, microcephaly, and endocrine dysfunction (PMID: 25728776, 25839420). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208515). For these reasons, this variant has been classified as Pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000190522	SCV001423854	likely pathogenic	Short stature, microcephaly, and endocrine dysfunction		criteria provided, single submitter	research	XRCC4 c.25delC, [p.H9fs] is a frameshift variant predicted to result in premature truncation or absence of XRCC4 protein. This variant has previously been reported in microcephaly and prenatal-onset global growth failure and is considered likely pathogenic (PMID:25728776; 25839420).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190522	SCV001653016	pathogenic	Short stature, microcephaly, and endocrine dysfunction	2020-06-27	criteria provided, single submitter	clinical testing	The p.His9ThrfsX8 variant in XRCC4 has been reported in the compound heterozygous state in 4 individuals with clinical features of primordial microcephalic dwarfism and segregated with disease in 1 affected relative (Murray 2015 PMID: 25728776, Rosin 2015 PMID: 25839420). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 208515) and been identified in 0.083% (107/128924) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 9 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the XRCC4 gene has been strongly associated with short stature, microcephaly, and endocrine dysfunction. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive short stature, microcephaly, and endocrine dysfunction. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP1.
Fulgent Genetics, Fulgent Genetics	RCV000190522	SCV001752698	likely pathogenic	Short stature, microcephaly, and endocrine dysfunction	2021-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000190522	SCV002766451	pathogenic	Short stature, microcephaly, and endocrine dysfunction	2022-11-22	criteria provided, single submitter	clinical testing	Variant summary: XRCC4 c.25delC (p.His9ThrfsX8) 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. Truncations downstream of this position are classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.00039 in 251062 control chromosomes. c.25delC has been reported in the literature in individuals affected with Microcephaly, primordial dwarfism, and unilateral renal agenesis (Murray_2015, Rosin_2015), and these individuals were reported as compound heterozygous, carrying other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000594218	SCV004159047	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	XRCC4: PVS1, PM2
OMIM	RCV000190522	SCV000245408	pathogenic	Short stature, microcephaly, and endocrine dysfunction	2015-07-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000594218	SCV002035071	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000594218	SCV002038423	pathogenic	not provided		no assertion criteria provided	clinical testing