ClinVar Miner

Submissions for variant NM_031475.3(ESPN):c.2230G>A (p.Asp744Asn)

gnomAD frequency: 0.00013  dbSNP: rs121908135
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757225 SCV000885371 uncertain significance not provided 2018-02-20 criteria provided, single submitter clinical testing The p.Asp744Asn variant (rs121908135) was reported in one patient with severe bilateral sensorineural hearing loss, and transfection of this variant in epithelial cell culture resulted in about 10 times higher presence of irregular microvilli patches compared to wild-type (Donaudy 2006). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.04 percent in the European Non-Finnish population (identified on 44 out of 117,486 chromosomes) and has been reported to the ClinVar database (Variation ID: 4421). The aspartic acid at position 744 is highly conserved and computational analyses of the effects of the p.Asp744Asn variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Asp744Asn variant with certainty.
GeneDx RCV000757225 SCV001830646 uncertain significance not provided 2022-03-15 criteria provided, single submitter clinical testing Observed in unrelated individuals with sensorineural hearing loss in published literature (Donaudy et al., 2006; Garcia-Garcia et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15930085, 33297549)
Fulgent Genetics, Fulgent Genetics RCV002490311 SCV002788085 uncertain significance Autosomal recessive nonsyndromic hearing loss 36; Usher syndrome, type 1M 2022-03-09 criteria provided, single submitter clinical testing
Invitae RCV000757225 SCV003259490 uncertain significance not provided 2022-08-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 744 of the ESPN protein (p.Asp744Asn). This variant is present in population databases (rs121908135, gnomAD 0.04%). This missense change has been observed in individual(s) with ESPN-related conditions (PMID: 15930085, 33297549). ClinVar contains an entry for this variant (Variation ID: 4421). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ESPN function (PMID: 15930085). 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.
OMIM RCV000004671 SCV000024845 pathogenic Deafness, without vestibular involvement, autosomal dominant 2006-02-01 no assertion criteria provided literature only

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