ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.131G>A (p.Trp44Ter) (rs104894413)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169176 SCV000220409 likely pathogenic Deafness, autosomal recessive 1A 2014-06-12 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000517231 SCV000227321 pathogenic not provided 2015-05-20 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000169176 SCV000599731 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515211 SCV000611267 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000517231 SCV000613505 pathogenic not provided 2015-07-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169176 SCV000698229 pathogenic Deafness, autosomal recessive 1A 2017-08-08 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.131G>A (p.Trp44X) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.139G>T [p.Glu47X], c.167delT [p.Leu56fsX26], and c.169C>T [p.Gln57X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and in control cohorts from the literature at a frequency of 0.0000082 (1/121870 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant has been identified in numerous patients reported in the literature in compound heterozygosity with known pathogenic GJB2 variants and as a homozygous allele (e.g., Carranza_CG_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic and pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000624765 SCV000741870 pathogenic Inborn genetic diseases 2016-11-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000517231 SCV000885519 pathogenic not provided 2018-02-09 criteria provided, single submitter clinical testing The p.Trp44Ter (rs104894413) is one of a commonly observed variants associated with nonsyndromic sensorineural hearing loss (Tang 2006, Carranza 2015, Snoeckx 2005, Putcha 2007, Lipan 2011, Roux 2004). In a large North American cohort it was determined as the sixth most common variant in individuals with African descent (Putcha 2007), and was reported as the most common variant observed in unrelated deaf families from Guatemala consistent with a founder effect in the Mayan population (Carranza 2015). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.02 percent in the Latino population (identified on 6 out of 33,574 chromosomes) and is listed in the Clinvar database with a pathogenic classification (Variation ID: 188830). The c.131G>A variant creates a premature stop in the GJB2 protein at codon 44 in exon 2/2 which results in a truncated or absent protein product. Based on these observations, the p.Trp44Ter variant is considered to be pathogenic.
GeneDx RCV000517231 SCV000890303 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing The W44X nonsense variant in the GJB2 gene has been reported previously in association with autosomal recessive nonsyndromic hearing loss when present in the homozygous state or with another pathogenic variant (Tang et al., 2006; Carranza et al., 2015). This variant is predicted to cause loss of normal protein function through protein truncation. The W44X variant is observed in 6/33574 alleles (0.0179%) from individuals of Latino background in large population cohorts (Lek et al., 2016). We interpret W44X as a pathogenic variant.
OMIM RCV000169176 SCV000280012 pathogenic Deafness, autosomal recessive 1A 2016-10-16 no assertion criteria provided literature only

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