Variant: NM_000260.4(MYO7A):c.1817G>A (p.Arg606His)

CA6197622

517357 (ClinVar)

Gene: MYO7A

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: afa3b665-0c01-40e2-9432-4938ce1c8bff

HGVS expressions

NM_000260.4:c.1817G>A
NM_000260.4(MYO7A):c.1817G>A (p.Arg606His)
NC_000011.10:g.77172767G>A
CM000673.2:g.77172767G>A
NC_000011.9:g.76883813G>A
CM000673.1:g.76883813G>A
NC_000011.8:g.76561461G>A
NG_009086.1:g.49504G>A
NG_009086.2:g.49522G>A
ENST00000409709.9:c.1817G>A
ENST00000669443.1:c.181G>A
ENST00000409619.6:c.1784G>A
ENST00000409709.7:c.1817G>A
ENST00000409893.5:c.1817G>A
ENST00000458637.6:c.1817G>A
ENST00000620575.4:c.1817G>A
NM_000260.3:c.1817G>A
NM_001127179.2:c.1817G>A
NM_001127180.1:c.1817G>A
NM_001127180.2:c.1817G>A
NM_001369365.1:c.1784G>A

Uncertain Significance

• Met criteria codes: PP3 PM3

• Not Met criteria codes: PVS1 BA1 BP5 BP7 BP2 BP3 BP1 BP4 BS2 BS4 BS3 BS1 PP4 PP1 PP2 PM1 PM4 PM5 PM6 PM2 PS2 PS4 PS3 PS1

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

Evidence submitted by expert panel

Hearing Loss VCEP

The c.1817 G>A (NM_000260.4(MYO7A):c.1817G>A (p.Arg606His)) variant in MYO7A is a missense variant predicted to cause substitution of Arginine by Histidine at amino acid 606. The highest major allele frequency in gnomAD v2.1.1 is 0.00035 (0.035 % or 8/23092 alleles) in the South Asian population (PM2_supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.832, (which is above the threshold of 0.7), evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least one individual with autosomal recessive nonsyndromic genetic hearing loss. This proband was compound heterozygous for the variant and a pathogenic variant, confirmed in trans by parental testing (PM3; 1.0 point; LMM Internal Data). The patient with this variant displayed moderate to severe sensorineural hearing loss, although no vision anomalies or difficulty seeing at night were noted (PP4 not met; LMM Internal Data). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive nonsyndromic genetic deafness, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: (PP3, PM3; Version 2, 7.19.2023).

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.832, (which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3).
• PM3: This variant has been detected in at least one individual with autosomal recessive nonsyndromic genetic hearing loss. This proband was compound heterozygous for the variant and a pathogenic variant, confirmed in trans by parental testing (PM3; 1.0 point; LMM Internal Data).

Not Met criteria codes

• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: REVEL score is 0.832.
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: The patient had congenital progressive moderately severe to severe sensorineural hearing loss and delayed walking. The proband was 16 at time of testing, and had normal eye exam and could see reasonably at night (LMM internal data; PP4 not met).
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: The highest major allele frequency in gnomAD v2.1.1 is 0.00035 (0.035 % or 8/23092 alleles) in the South Asian population (PM2_supporting, BS1, BA1 not met).
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2023-07-19

Published on: 2023-10-05