Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • See Evidence submitted by expert panel for details.

Variant: NM_004999.3(MYO6):c.1025C>T (p.Ala342Val)

CA135587

45131 (ClinVar)

Gene: MYO6
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e877db5b-e7aa-4792-865f-538037682cc8
Approved on: 2019-03-25
Published on: 2019-07-17

HGVS expressions

NM_004999.3:c.1025C>T
NM_004999.3(MYO6):c.1025C>T (p.Ala342Val)
NC_000006.12:g.75848478C>T
CM000668.2:g.75848478C>T
NC_000006.11:g.76558195C>T
CM000668.1:g.76558195C>T
NC_000006.10:g.76614915C>T
NG_009934.1:g.104287C>T
NG_009934.2:g.104286C>T
NM_001300899.1:c.1025C>T
NM_004999.4:c.1025C>T
ENST00000369975.5:c.1025C>T
ENST00000369977.7:c.1025C>T
ENST00000369981.7:c.1025C>T
ENST00000369985.8:c.1025C>T
ENST00000615563.4:c.1025C>T
ENST00000627432.2:c.1025C>T

Benign

Met criteria codes 2
BA1 PP3
Not Met criteria codes 10
PVS1 BP4 BP3 BP7 PS1 PS4 PP4 PM2 PM5 PM4

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The filtering allele frequency of the p.Ala342Val variant in the MYO6 gene is 0.21% for European (non-Finnish) chromosomes by gnomAD (304/129090 with 95% CI), and one homozygous European (Finnish) individual, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). The REVEL computational prediction analysis tool produced a score of 0.905, however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, the HL EP classified this variant as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1.
Met criteria codes
BA1
The filtering allele frequency of the p.Ala342Val variant in the MYO6 gene is 0.21% for European (non-Finnish) chromosomes by gnomAD (304/129090 with 95% CI), and one homozygous European (Finnish) individual, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1).
PP3
The REVEL computational prediction analysis tool produced a score of 0.905, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own.
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
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
BP7
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
PS4
The variant has been observed in six hearing loss individuals at Partners LMM, two additional HL patients carrying the variant in het. have alternate cause of disease. The variant has also been observed in 2 individuals by Praxis fuer Humangenetick Tuebingen and one individual by EGL Diagnostics.
131 patients tested with targeted enrichment of selected genes. Inclusion criteria: parent’s have normal hearing; patient is of Western-European ethnicity; syndromic hearing loss has been excludes by a clinical geneticist or an otolaryngologist with clinical genetics training; nonsyndromic, sensorineural, mild to profound, symmetric HL; GJB2 variants have been excluded. one patient carries the p.Ala342Val variant in het., as well as heterozygous MYO6 p.Arg946Cys (Approved as LB by ClinGen HL VCEP), PDCH15 p.Arg1911His (VUS in ClinVar) and CDH23 p.Arg3109His variants (VUS in ClinVar) PubMed:27068579
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
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
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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