Variant: NM_206933.2(USH2A):c.3902G>T (p.Gly1301Val)

CA143472

48509 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 705d0fbc-b15a-4fc0-9f5e-c1ead022e87e

Approved on: 2019-03-13

Published on: 2019-10-18

HGVS expressions

NM_206933.2:c.3902G>T
NM_206933.2(USH2A):c.3902G>T (p.Gly1301Val)
NC_000001.11:g.216198494C>A
CM000663.2:g.216198494C>A
NC_000001.10:g.216371836C>A
CM000663.1:g.216371836C>A
NC_000001.9:g.214438459C>A
NG_009497.1:g.229903G>T
NG_009497.2:g.229955G>T
ENST00000307340.8:c.3902G>T
ENST00000674083.1:c.3902G>T
ENST00000307340.7:c.3902G>T
ENST00000366942.3:c.3902G>T
NM_007123.5:c.3902G>T
NM_206933.3:c.3902G>T
NM_007123.6:c.3902G>T
NM_206933.4:c.3902G>T

Benign

• Met criteria codes: BA1

• Not Met criteria codes: PM2 PS1 PS4 PM1 PM3 PM5 PP2 PP3 BP4 BP1

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The filtering allele frequency of the p.Gly1301Val variant in the USH2A gene is 0.52% for South Asian chromosomes by gnomAD (183/30608 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome variants (BA1).

Met criteria codes

• BA1: The filtering allele frequency of the p.Gly1301Val variant in the USH2A gene is 0.52% for South Asian chromosomes by gnomAD (183/30608 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome variants (BA1).

Not Met criteria codes

• PM2: 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: Additional patient with retinitis pigmentosa is homozygous for the p.Gly1301Val variant. This is from a document titled "Chapter 2.3 Hearing in patients with USH2A-associated nsRP". PMID is not available to enter into the Curated Literature Evidence section. Partners LMM reported one proband with moderately-severe mid-frequency SNHL, and a sibling with congenital hearing loss. Proband carries the p.Gly1301Val variant in heterozygosity, but the sibling does not carry the variant (SCB000065531.5). Praxis feur Humangenetic Tuebingen reported two probands with retinal phenotypes who carried the variant. Alternate causes of disease were identified (SCV000574821.4). PS4 is not applied because a 2x2 contingency table was made using the 1 South Asian case, out of 457 affected from the paper, versus the 184 of 30778 South Asian controls.
• PM1: HL VCEP has not specified any mutational hotspots in USH2A.
• PM3: The p.G1301V variant was reported in compound het. with a p.R878H USH2A variant, with retinal degeneration. The p.R878H variant has been reported as benign by the Partners LMM and is present in gnomAD in 470/30616 South Asian alleles in gnomAD.
• PM5: 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
• PP3: The REVEL score is 0.218 which is not high enough to meet PP3.
• BP4: The REVEL score is 0.218 which is not low enough to meet BP4.
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline