ClinVar Miner

Submissions for variant NM_005235.3(ERBB4):c.308G>A (p.Arg103His)

gnomAD frequency: 0.00033  dbSNP: rs754487821
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University RCV001095485 SCV001251079 benign Amyotrophic lateral sclerosis 2020-03-31 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV002554875 SCV003269303 uncertain significance not provided 2024-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 103 of the ERBB4 protein (p.Arg103His). This variant is present in population databases (rs754487821, gnomAD 0.009%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) (PMID: 29895397). ClinVar contains an entry for this variant (Variation ID: 873273). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ERBB4 protein function with a negative predictive value of 80%. 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.
PreventionGenetics, part of Exact Sciences RCV003396744 SCV004104108 uncertain significance ERBB4-related disorder 2024-01-22 no assertion criteria provided clinical testing The ERBB4 c.308G>A variant is predicted to result in the amino acid substitution p.Arg103His. This variant was reported in two individuals with amyotrophic lateral sclerosis (ALS); however, one of the individuals also carried a pathogenic variant in an ALS-associated gene providing the diagnosis (Table 1, Narain et al. 2018. PubMed ID: 29895397; eTable 1 and eTable 2A, Grassano et al. 2022. PubMed ID: 35896380). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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