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_004004.5:c.674C>T

CA387460667

555720 (ClinVar)

Gene: GJB2
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: b93f946a-ef2d-4b2a-9bd3-adc60da6f546
Approved on: 2018-09-20
Published on: 2019-07-17

HGVS expressions

NM_004004.5:c.674C>T
NC_000013.11:g.20188908G>A
CM000675.2:g.20188908G>A
NC_000013.10:g.20763047G>A
CM000675.1:g.20763047G>A
NC_000013.9:g.19661047G>A
NG_008358.1:g.9068C>T
NM_004004.6:c.674C>T
ENST00000382844.1:c.674C>T
ENST00000382848.4:c.674C>T

Uncertain Significance

Met criteria codes 2
PM3 PM2
Not Met criteria codes 21
BA1 BP4 BP2 BP3 BP7 BP5 BS2 BS1 BS4 PVS1 PP3 PP4 PP1 PS3 PS2 PS4 PS1 PM4 PM1 PM5 PM6

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The p.Pro225Leu variant in GJB2 is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). This variant has been detected in 1 patient with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3; PMID:21112098). In summary, this variant meets criteria to be classified as a variant of uncertain clinical significance for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3.
Met criteria codes
PM3
p.Pro225Leu variant was found in trans with the common p.G45E/p.Y136X allele common in the Japanese population in a proband with profound deafness. The p.G45E variant on its own causes lethal dominant KID syndrome but the nonsense variant "protects" from this more severe phenotype. Confirmed in trans
p.Pro225Leu variant was found in trans with the common p.G45E/p.Y136X allele common in the Japanese population in a proband with profound deafness. The p.G45E variant on its own causes lethal dominant KID syndrome but the nonsense variant "protects" from this more severe phenotype. Confirmed in trans PubMed:21112098
PM2
Variant p.Pro225Leu is absent from gnomAD
Not Met criteria codes
BA1
Variant p.Pro225Leu is absent from gnomAD
BP4
Revel score was 0.586, which does not meet cutoff of 0.7
BP2
p.Pro225Leu variant was found in trans with the common p.G45E/p.Y136X allele common in the Japanese population in a proband with profound deafness. The p.G45E variant on its own causes lethal dominant KID syndrome but the nonsense variant "protects" from this more severe phenotype. Confirmed in trans PubMed:21112098
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
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Variant p.Pro225Leu is absent from gnomAD
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Revel score was 0.586, which does not meet cutoff of 0.7
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
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
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
PS1
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
PM1
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
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