Submissions for variant NM_000260.4(MYO7A):c.3503G>A (p.Arg1168Gln)

gnomAD frequency: 0.00004  dbSNP: rs797044516

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001004779	SCV001164262	pathogenic	Usher syndrome	2019-09-16	reviewed by expert panel	curation	The c.3503G>A (p.Arg1168Gln) variant in MYO7A has been detected in at least 4 probands with Usher syndrome. For two of those probands, a pathogenic or suspected-pathogenic variants was observed in trans, and in one individual, the variant was observed with a pathogenic or suspected-pathogenic variant, but it was unclear if phasing was performed (PM3_Strong, PP4; PMID:25404053, 27460420, 28944237). The allele frequency of this variant is 0.004%% (1/26850) of South Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The c.3503G>A (p.Arg1168Gln) variant is located in the last base of the exon, which is part of the 5' consensus sequence, and computational tools suggest an impact to splicing. Furthermore, tThe REVEL computational prediction analysis tool produced a score of 0.9, which is above the threshold necessary to apply PP3. A different likely pathogenic or suspected-pathogenic variant at the same nucleotide (c.3503G>C, Arg1168Pro) has been previously identified in an individual with Usher syndrome who was compound heterozygous for a second pathogenic truncating variant (PMID: 16470552). In addition, a minigene assay demonstrated that the 3503G>C variant led to skipping of exon 27 (PMID: 20052763) suggesting that variants that alter the c.3503G nucleotide may cause abnormal splicing (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Strong, PP4, PM2, PP3, PM5_Supporting.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156269	SCV000205986	uncertain significance	not specified	2014-01-03	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The 3503G>A (Ar g1168Gln) variant in MYO7A has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the f requency of this variant. This variant is located in the last base of exon 27 in the major transcript (NM_000260.3) of MYO7A, which is part of the conserved 5? splice region of intron 27. Computational tools suggest an impact to splicing; h owever, this information is not predictive enough to determine pathogenicity. Ho wever, a different variant at the same nucleotide (3503G>C, Arg1168Pro) has been previously described in an individual with Usher syndrome who was compound hete rozygous for a second pathogenic variant (Jaijo 2006). Functional studies demons trated that the 3503G>C variant led to skipping of exon 27 (Le Guedard-Mereuze 2 010), suggesting that variants that alter the c.3503G nucleotide cause abnormal splicing. In summary, the clinical significance of this variant cannot be determ ined with certainty; however based upon its location within the splice consensus sequence and its predicted impact on splicing, we would lean towards a more lik ely pathogenic role.
Ambry Genetics	RCV000623408	SCV000741576	pathogenic	Inborn genetic diseases	2016-06-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000675162	SCV000800779	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2017-08-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091732	SCV001247935	pathogenic	not provided	2017-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV001091732	SCV001398407	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1168 of the MYO7A protein (p.Arg1168Gln). This variant also falls at the last nucleotide of exon 27, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive Usher syndrome (PMID: 25404053, 27460420, 28944237). ClinVar contains an entry for this variant (Variation ID: 179479). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001004779	SCV004030132	pathogenic	Usher syndrome	2023-07-25	criteria provided, single submitter	clinical testing	Variant summary: MYO7A c.3503G>A (p.Arg1168Gln) results in a conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence . This variant also locates in the last base of exon 27, which is part of the 5' consensus splice region. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the 5 splicing donor site. Two predict the variant weakens the 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.1e-06 in 196868 control chromosomes in gnomAD. c.3503G>A has been reported in the literature in multiple individuals affected with Usher Syndrome, including being compound heterozygous state with five different pathogenic/likely pathogenic variants in at-least five Usher Syndrome cases and being homozygous in at-least one Usher Syndrome case (example: Aparisi_2014, Dad_2016, Fuster-Garcia_2018, Neuhaus_2017, Weisschuh_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25404053, 27957503, 30459346, 28944237, 32531858). Five submitters including the ClinGen Hearing Loss Variant Curation Expert Panel have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.