ClinVar Miner

Submissions for variant NM_000264.5(PTCH1):c.4141G>A (p.Val1381Met) (rs187104739)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200618 SCV000254474 likely benign Gorlin syndrome 2020-11-16 criteria provided, single submitter clinical testing
GeneDx RCV000489808 SCV000576759 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PTCH1 gene. The V1381M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1381M variant is observed in 5/63768 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the V1381M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000567164 SCV000674469 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-30 criteria provided, single submitter clinical testing The p.V1381M variant (also known as c.4141G>A), located in coding exon 23 of the PTCH1 gene, results from a G to A substitution at nucleotide position 4141. The valine at codon 1381 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780653 SCV000918101 likely benign not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: PTCH1 c.4141G>A (p.Val1381Met) results in a conservative amino acid change located outside of any known functional domain or repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 243022 control chromosomes. The observed variant frequency is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTCH1 causing Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) phenotype (1.7e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4141G>A in individuals affected with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000200618 SCV001330971 uncertain significance Gorlin syndrome 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 Clinical Services Laboratory,Illumina RCV001168387 SCV001330972 uncertain significance Holoprosencephaly 7 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.

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