Submissions for variant NM_000260.4(MYO7A):c.4115T>G (p.Val1372Gly)

dbSNP: rs869312181

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171542	SCV001334327	uncertain significance	Usher syndrome	2020-04-29	reviewed by expert panel	curation	The c.4115T>G (p.Val1372Gly) variant in MYO7A is absent from gnomAD (PM2). The REVEL computational prediction analysis tool produced a score of 0.869, which is above the threshold necessary to apply PP3. While this variant was reported with a second loss of function variant in MYO7A in an inherited retinal disease cohort that includes Usher syndrome patients, it was unclear whether the patient with these variants had Usher syndrome or if the variants were in trans (PM3 not met; PMID: 26872967, SCV000259091.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PP3.
Invitae	RCV002515581	SCV003441018	likely pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing	This variant disrupts the p.Val1372 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 26872967, 31836858, 33576163), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 224749). This missense change has been observed in individual(s) with Usher syndrome (PMID: 26872967, 31836858). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1372 of the MYO7A protein (p.Val1372Gly). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210299	SCV000259091	likely pathogenic	Usher syndrome type 1	2015-01-30	no assertion criteria provided	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000225646	SCV000282591	uncertain significance	Retinal dystrophy		no assertion criteria provided	clinical testing