chr11-77159450-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS1_SupportingBP2
This summary comes from the ClinGen Evidence Repository: The c.1007G>A (p.Arg336His) variant in MYO7A was present in 0.20% (284/127730) non-Finnish European alleles in gnomAD v2.1 which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). It was identified in the homozygous state in 2 individuals, one of which was beyond the average age of onset for Usher syndrome. The variant was detected in an individual with Usher syndrome in whom a second variant was not found (PMID:16470552). It was also identified in 2 patients with severe sensorineural hearing loss and Retinitis pigmentosa who carried other pathogenic or likely pathogenic variants thought to be causative of disease (BP2; SCV000059690.6; ClinVar IDs: 43340, 43223, 2351, 48449). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. The c.1007G>A (Arg336His) variant was also assessed for autosomal dominant non-syndromic hearing loss. This resulted in a benign classification ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BS4, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA132194/MONDO:0019501/005
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MYO7A | ENST00000409709.9 | c.1007G>A | p.Arg336His | missense_variant | Exon 10 of 49 | 1 | NM_000260.4 | ENSP00000386331.3 | ||
MYO7A | ENST00000458637.6 | c.1007G>A | p.Arg336His | missense_variant | Exon 10 of 49 | 1 | ENSP00000392185.2 | |||
MYO7A | ENST00000409619.6 | c.974G>A | p.Arg325His | missense_variant | Exon 11 of 50 | 1 | ENSP00000386635.2 |
Frequencies
GnomAD3 genomes AF: 0.00162 AC: 210AN: 129680Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.00116 AC: 288AN: 247514Hom.: 1 AF XY: 0.00105 AC XY: 141AN XY: 134430
GnomAD4 exome AF: 0.00234 AC: 2822AN: 1204636Hom.: 4 Cov.: 35 AF XY: 0.00230 AC XY: 1372AN XY: 597724
GnomAD4 genome AF: 0.00162 AC: 210AN: 129732Hom.: 0 Cov.: 29 AF XY: 0.00151 AC XY: 92AN XY: 61010
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
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This variant is associated with the following publications: (PMID: 30311386, 30245029, 15221449, 16470552, 25262649) -
Autosomal dominant nonsyndromic hearing loss 11 Uncertain:1Benign:1
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,PP3. -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Usher syndrome type 1 Uncertain:1Benign:1
NM_000260.3(MYO7A):c.1007G>A(R336H) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. R336H has been observed in cases with relevant disease (PMID: 23804846, 16470552, 33363762). Functional assessments of this variant are not available in the literature. R336H has been observed in population frequency databases (gnomAD: NFE 0.22%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.1007G>A(R336H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not specified Benign:2
p.Arg336His in exon 10 of MYO7A: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (125/66438) of European chrom osomes including 1 homozygous individual by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs45629132). This variant has been re ported in the literature; however, there is no evidence to support pathogenicity . It was identified in a family with autosomal dominant hearing loss but found n ot to segregate with disease and therefore assumed to be benign (Luijendijk 2004 ). It was also identified in the heterozygous state in a proband with Usher synd rome without a second variant (Jaijo 2006). -
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Meniere disease Uncertain:1
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Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
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Autosomal recessive nonsyndromic hearing loss 2 Benign:1
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Usher syndrome Benign:1
The c.1007G>A (p.Arg336His) variant in MYO7A was present in 0.20% (284/127730) non-Finnish European alleles in gnomAD v2.1 which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). It was identified in the homozygous state in 2 individuals, one of which was beyond the average age of onset for Usher syndrome. The variant was detected in an individual with Usher syndrome in whom a second variant was not found (PMID: 16470552). It was also identified in 2 patients with severe sensorineural hearing loss and Retinitis pigmentosa who carried other pathogenic or likely pathogenic variants thought to be causative of disease (BP2; SCV000059690.6; ClinVar IDs: 43340, 43223, 2351, 48449). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. The c.1007G>A (Arg336His) variant was also assessed for autosomal dominant non-syndromic hearing loss. This resulted in a benign classification ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BS4, BP2. -
Usher syndrome type 1B Benign:1
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MYO7A-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at