Submissions for variant NM_000124.4(ERCC6):c.4393G>A (p.Val1465Ile) (rs201813523)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000316584	SCV000362731	uncertain significance	Age-related macular degeneration 5	2018-01-12	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 Clinical Services Laboratory,Illumina	RCV000375860	SCV000362732	uncertain significance	Cockayne syndrome B	2018-01-12	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 Clinical Services Laboratory,Illumina	RCV000262594	SCV000362733	uncertain significance	Cerebrooculofacioskeletal syndrome 1	2018-01-12	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.
GeneDx	RCV000483087	SCV000574110	uncertain significance	not provided	2018-11-05	criteria provided, single submitter	clinical testing	The V1465I variant in the ERCC6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state in any controls, the V1465I variant is observed in 5/11,574 alleles (0.04%) from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The V1465I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and this substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V1465I as a variant of uncertain significance.
Invitae	RCV000483087	SCV001012562	likely benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing