Submissions for variant NM_001079.4(ZAP70):c.1645A>G (p.Met549Val)

gnomAD frequency: 0.00036  dbSNP: rs150950017

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000297141	SCV000432693	uncertain significance	Combined immunodeficiency due to ZAP70 deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055985	SCV001220401	uncertain significance	ZAP70-Related Severe Combined Immunodeficiency	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 549 of the ZAP70 protein (p.Met549Val). This variant is present in population databases (rs150950017, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with ZAP70-related conditions. ClinVar contains an entry for this variant (Variation ID: 337637). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508451	SCV001714606	uncertain significance	not provided	2021-01-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504136	SCV002815591	uncertain significance	Combined immunodeficiency due to ZAP70 deficiency; Autoimmune disease, multisystem, infantile-onset, 2	2024-03-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021824	SCV004982386	uncertain significance	Inborn genetic diseases	2021-10-12	criteria provided, single submitter	clinical testing	The c.1645A>G (p.M549V) alteration is located in exon 13 (coding exon 11) of the ZAP70 gene. This alteration results from a A to G substitution at nucleotide position 1645, causing the methionine (M) at amino acid position 549 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV000297141	SCV001749551	not provided	Combined immunodeficiency due to ZAP70 deficiency		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
GenomeConnect, ClinGen	RCV001508451	SCV002075273	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.