Submissions for variant NM_003401.5(XRCC4):c.127T>C (p.Trp43Arg)

gnomAD frequency: 0.00002  dbSNP: rs587779351

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000343573	SCV000329994	pathogenic	not provided	2016-12-13	criteria provided, single submitter	clinical testing	The W43R pathogenic variant in the XRCC4 gene has been reported previously in the homozygous state in at least two individuals with microcephalic primordial dwarfism (Shaheen et al., 2014; Murray et al., 2015). Functional studies demonstrate that this variant impairs XRCC4 function and results in greatly reduced protein levels as compared to wild type (Murray et al., 2015; Guo et al., 2015). The W43R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret W43R as a pathogenic variant.
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV000190521	SCV001438862	likely pathogenic	Short stature, microcephaly, and endocrine dysfunction		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000343573	SCV001448078	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000115044	SCV000108409	pathogenic	Ateleiotic dwarfism		no assertion criteria provided	research
OMIM	RCV000190521	SCV000245407	pathogenic	Short stature, microcephaly, and endocrine dysfunction	2015-07-23	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004748579	SCV005342954	pathogenic	XRCC4-related disorder	2024-07-23	no assertion criteria provided	clinical testing	The XRCC4 c.127T>C variant is predicted to result in the amino acid substitution p.Trp43Arg. This variant has been reported in the homozygous state in individuals with short stature and microcephaly (Shaheen et al. 2014. PubMed ID: 24389050; Shaheen et al. 2018. PubMed ID: 30214071; Asa et al. 2021. PubMed ID: 33842963). Functional studies showed that this variant impacts protein functions (Murray et al. 2015. PubMed ID: 25728776; Asa et al. 2021. PubMed ID: 33842963). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic