Submissions for variant NM_015404.4(WHRN):c.958C>T (p.Leu320Phe)

gnomAD frequency: 0.00004  dbSNP: rs780855079

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000529	SCV001157442	uncertain significance	not specified	2018-10-09	criteria provided, single submitter	clinical testing	The WHRN c.958C>T; p.Leu320Phe variant (rs780855079), to our knowledge, has not been reported in the medical literature or gene specific databases. This variant is found in the general population with an allele frequency in non-Finnish Europeans of 0.0004% (8/111,704 alleles) in the Genome Aggregation Database. The leucine at codon 320 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, based on the available information, the clinical significance of this variant is uncertain.
Invitae	RCV001052821	SCV001217050	uncertain significance	not provided	2022-06-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 320 of the WHRN protein (p.Leu320Phe). This variant is present in population databases (rs780855079, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 811003). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001168139	SCV001330710	uncertain significance	Autosomal recessive nonsyndromic hearing loss 31	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001168140	SCV001330711	uncertain significance	Usher syndrome type 2D	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV001052821	SCV004032873	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	WHRN: PM2