Submissions for variant NM_000260.4(MYO7A):c.6247G>A (p.Ala2083Thr)

gnomAD frequency: 0.00021  dbSNP: rs41298759

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155244	SCV000204930	likely benign	not specified	2020-01-15	criteria provided, single submitter	clinical testing	The p.Ala2083Thr variant in MYO7A is classified as likely benign because it has been identified in 0.2% (18/10348) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org), and computational prediction tools and conservation analysis suggest that this variant may not impact the protein. ACMG/AMP criteria applied: BS1_Supporting, BP4.
Illumina Laboratory Services, Illumina	RCV000290561	SCV000374515	uncertain significance	Usher syndrome type 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001089552	SCV000374516	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000386123	SCV000374517	likely benign	Autosomal dominant nonsyndromic hearing loss 11	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Fulgent Genetics, Fulgent Genetics	RCV000765019	SCV000896203	uncertain significance	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034255	SCV001197587	likely benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089552	SCV001244763	uncertain significance	Autosomal recessive nonsyndromic hearing loss 2	2018-06-26	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_000260.3(MYO7A):c.6247G>A, has been identified in exon 46 of 49 of the MYO7A gene. The variant is predicted to result in a minor amino acid change from alanine to threonine at position 2083 of the protein (NP_000251.3(MYO7A):p.(Ala2083Thr)). The alanine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the FERM functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.036% (99 heterozygotes, 1 homozygote). The variant has been previously described as a Variant of Unknown Significance (ClinVar, Deafness Variation Database). Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.
Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)	RCV001526687	SCV001451444	uncertain significance	Meniere disease	2020-12-14	criteria provided, single submitter	case-control
GeneDx	RCV001034255	SCV001765712	uncertain significance	not provided	2020-09-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
CeGaT Center for Human Genetics Tuebingen	RCV001034255	SCV002585338	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001034255	SCV003799759	uncertain significance	not provided	2022-05-05	criteria provided, single submitter	clinical testing	The MYO7A c.6247G>A; p.Ala2083Thr variant (rs41298759), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 178496). This variant is found in the Ashkenazi Jewish population with an allele frequency of 0.1% (18/10348 alleles) in the Genome Aggregation Database. The alanine at codon 2083 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.276). Due to limited information, the clinical significance of the p.Ala2083Thr variant is uncertain at this time.
Ambry Genetics	RCV004019859	SCV004952112	uncertain significance	Inborn genetic diseases	2021-08-02	criteria provided, single submitter	clinical testing	The c.6247G>A (p.A2083T) alteration is located in exon 46 (coding exon 45) of the MYO7A gene. This alteration results from a G to A substitution at nucleotide position 6247, causing the alanine (A) at amino acid position 2083 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001274807	SCV001459298	uncertain significance	Usher syndrome type 1B	2020-04-17	no assertion criteria provided	clinical testing