Submissions for variant NM_000260.4(MYO7A):c.6326C>T (p.Thr2109Ile)

gnomAD frequency: 0.00004  dbSNP: rs377670513

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001089684	SCV001245168	likely pathogenic	Usher syndrome	2023-01-18	reviewed by expert panel	curation	The variant NM_000260.4:c.6326C>T in MYO7A is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 2109 (p.Thr2109Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (8/128408 alleles, 0 homozygotes) for the European (Non-Finnish) population, which meets PM2_supporting criteria. The REVEL computational prediction analysis tool produced a score of 0.821, meeting PP3 criteria. This variant has been reported in two unrelated probands, both with Usher syndrome (PP4; SCV000199631.4). In addition, both probands had an additional MYO7A pathogenic or likely pathogenic variant in trans, meeting PM3_Strong criteria. Finally, the variant was shown to segregate with two affected family members (PP1_Moderate). In summary, the variant meets criteria to be classified as likely pathogenic for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: PM2_supporting, PP3, PP4, PM3_Strong, PP1_Moderate (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151522	SCV000199631	likely pathogenic	Rare genetic deafness	2017-07-25	criteria provided, single submitter	clinical testing	The p.Thr2109Ile variant in MYO7A has been identified by our laboratory in two u nrelated individuals with clinical features of Usher syndrome and segregated in two affected family members. In both families, a second MYO7A variant was identi fied on the remaining copy of the gene. The age of onset of the retinitis pigmen tosa in two siblings was reported to be in the mid to late 30s, which is atypica l for classic type 1 Usher syndrome. The two affected siblings in the other fami ly presented hearing loss but no reported vision findings at the age under 5. Th e p.Thr2109Ile variant has been identified in 8/126680 European chromosomes and 1/24022 African chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs377670513); however, its frequency is low enou gh to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Thr2109Ile variant may impac t the protein. In summary, although additional studies are required to fully est ablish its clinical significance, the p.Thr2109Ile variant is likely pathogenic.
Eurofins Ntd Llc (ga)	RCV000591925	SCV000705142	uncertain significance	not provided	2017-01-09	criteria provided, single submitter	clinical testing
Invitae	RCV000591925	SCV002148212	pathogenic	not provided	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2109 of the MYO7A protein (p.Thr2109Ile). This variant is present in population databases (rs377670513, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of autosomal recessive MYO7A associated conditions (Invitae; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164724). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000591925	SCV002586611	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (ClinVar Variant ID 164724; ClinVar); This variant is associated with the following publications: (PMID: 33671976)