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

gnomAD frequency: 0.00002  dbSNP: rs587779351

Total submissions: 5

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
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & 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