17-50194019-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2
The NM_000088.4(COL1A1):c.1691G>A(p.Arg564His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,613,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R564C) has been classified as Likely benign.
Frequency
Consequence
NM_000088.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.1691G>A | p.Arg564His | missense_variant | 25/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.1493G>A | p.Arg498His | missense_variant | 22/48 | ||
COL1A1 | XM_005257058.5 | c.1691G>A | p.Arg564His | missense_variant | 25/49 | ||
COL1A1 | XM_005257059.5 | c.958-1326G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.1691G>A | p.Arg564His | missense_variant | 25/51 | 1 | NM_000088.4 | P1 | |
COL1A1 | ENST00000463440.1 | n.81G>A | non_coding_transcript_exon_variant | 3/3 | 2 | ||||
COL1A1 | ENST00000471344.1 | n.723G>A | non_coding_transcript_exon_variant | 8/8 | 2 | ||||
COL1A1 | ENST00000476387.1 | n.40G>A | non_coding_transcript_exon_variant | 1/9 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 151904Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251298Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135874
GnomAD4 exome AF: 0.000246 AC: 359AN: 1461304Hom.: 0 Cov.: 31 AF XY: 0.000250 AC XY: 182AN XY: 726944
GnomAD4 genome AF: 0.000197 AC: 30AN: 151904Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8AN XY: 74212
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, arthrochalasia type Uncertain:2Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 22, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Osteogenesis imperfecta type I Pathogenic:1Benign:1
Likely pathogenic, flagged submission | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2022 | Reported in an individual with features of a connective tissue disorder who underwent exome sequencing (Retterer et al., 2016); Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24273577, 26633542) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 23, 2019 | - - |
Ehlers-Danlos syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | May 02, 2022 | - - |
Infantile cortical hyperostosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2023 | The p.R564H variant (also known as c.1691G>A), located in coding exon 25 of the COL1A1 gene, results from a G to A substitution at nucleotide position 1691. The arginine at codon 564 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in an individual with features of connective tissue disease (Retterer K et al. Genet Med, 2016 07;18:696-704). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Osteogenesis imperfecta Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at