Submissions for variant NM_000260.4(MYO7A):c.397C>A (p.His133Asn)

gnomAD frequency: 0.00003  dbSNP: rs111033403

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151476	SCV000199541	uncertain significance	not specified	2016-08-04	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Counsyl	RCV000665283	SCV000789376	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2017-01-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054443	SCV001218757	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 133 of the MYO7A protein (p.His133Asn). This variant is present in population databases (rs111033403, gnomAD 0.008%). This missense change has been observed in individuals with Usher syndrome (PMID: 26969326; Invitae). ClinVar contains an entry for this variant (Variation ID: 164656). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. This variant disrupts the p.His133 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 16679490, 20052763), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001115094	SCV001273039	likely benign	Usher syndrome type 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001115095	SCV001273040	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001115096	SCV001273041	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001115095	SCV005398015	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2024-09-23	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness autosomal dominant 11 (MIM#601317), deafness autosomal recessive 2 (MIM#600060) and Usher syndrome, type 1B (MIM#276900). In addition, dominant negative is the suggested mechanism for missense variants in autosomal dominant inheritance (OMIM, PMID: 23383098). (I) 0108 - This gene is associated with both recessive and dominant disease. While the genotype-phenotype correlation is unestablished, missense variants causing autosomal dominant inheritance are rare and are not localised to a specific protein region (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin head motor domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(His133Tyr), p.(His133Asp) and p.(His133Gln) have been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. p.(His133Asp) also has an older VUS entry, and p.(His133Pro) has been classified as a VUS in ClinVar and pathogenic in the deafness variation database. p.(His133Tyr) and p.(His133Asp) have also been observed in individuals with a second MYO7A variant with Usher syndrome or profound hearing loss (PMID: 28944237, 35982127). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic in individuals with a second MYO7A variant with Usher syndrome or hearing loss (PMID: 37466950, 26969326, 36011334, DECIPHER). This variant has been classified as pathogenic once in ClinVar, as well as older VUS and likely benign entries. This variant has also been classified as pathogenic in the deafness variation database. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000260.3(MYO7A):c.133-2A>G) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV001831942	SCV002093114	uncertain significance	Usher syndrome type 1B	2020-12-18	no assertion criteria provided	clinical testing