Submissions for variant NM_206937.2(LIG4):c.2525C>A (p.Ala842Asp)

gnomAD frequency: 0.00129  dbSNP: rs72660870

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000383863	SCV000382191	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000272998	SCV000382192	uncertain significance	DNA ligase IV deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000272998	SCV000762711	likely benign	DNA ligase IV deficiency	2024-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763874	SCV000894809	uncertain significance	DNA ligase IV deficiency; Multiple myeloma	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000763874	SCV001468381	uncertain significance	DNA ligase IV deficiency; Multiple myeloma	2021-03-30	criteria provided, single submitter	clinical testing	LIG4 NM_002312.3 exon 2 p.Ala842Asp (c.2525C>A): This variant has not been reported in the literature but is present in 0.2% (274/129160) of European alleles, including 1 homozygote, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-108861092-G-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:310975). Evolutionary conservation for this variant suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV000857399	SCV001870984	uncertain significance	not provided	2022-08-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001820917	SCV002068855	uncertain significance	not specified	2021-04-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the LIG4 gene demonstrated a sequence change, c.2525C>A, in exon 2 that results in an amino acid change, p.Ala842Asp. This sequence change does not appear to have been previously described in individuals with LIG4-related disorders and has been described in the gnomAD database with a frequency of 0.21% in the European sub-population (dbSNP rs72660870). The p.Ala842Asp change affects a moderately conserved amino acid residue located in a domain of the LIG4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala842Asp substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala842Asp change remains unknown at this time.
PreventionGenetics, part of Exact Sciences	RCV003920295	SCV004742758	likely benign	LIG4-related condition	2020-09-29	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).