rs201737248
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The ENST00000613296.6(ALMS1):c.6707C>T(p.Pro2236Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2236T) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000613296.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.6707C>T | p.Pro2236Leu | missense_variant | 8/23 | ENST00000613296.6 | NP_001365383.1 | |
ALMS1 | NM_015120.4 | c.6710C>T | p.Pro2237Leu | missense_variant | 8/23 | NP_055935.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.6707C>T | p.Pro2236Leu | missense_variant | 8/23 | 1 | NM_001378454.1 | ENSP00000482968 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152042Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248570Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134894
GnomAD4 exome AF: 0.0000766 AC: 112AN: 1461728Hom.: 0 Cov.: 37 AF XY: 0.0000646 AC XY: 47AN XY: 727170
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152042Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74264
ClinVar
Submissions by phenotype
Alstrom syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Jun 10, 2021 | The p.Pro2237Leu (also referred to as p.Pro2235Leu) variant in the ALMS1 gene has not been previously reported in association with disease. This variant has been identified in 4/127,976 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that the p.Pro2237Leu variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Pro2237Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; BP4] - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 03, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 03, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2237 of the ALMS1 protein (p.Pro2237Leu). This variant is present in population databases (rs201737248, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 459880). 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. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jan 09, 2018 | This variant was identified in a heterozygous state in a patient with familial cardiomyopathy. SCICD Classification: Variant of uncertain significance based on lack of case data, poor genotype-phenotype match, only a heterozygous variant in a gene that causes autosomal recessive disease, and rarity in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: The ALMS1 gene is associated with autosomal RECESSIVE Alström syndrome. Alström syndrome includes cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated or restrictive cardiomyopathy, the insulin resistance syndrome, and multiple organ failure. There are 134 variant submissions for ALMS1 in ClinVar and 15 submissions specifically for cardiomyopathy. Five of these submissions are missense variants and considered “pathogenic†or “likely pathogenic.†Unfortunately, the submitters did not include supporting evidence or whether or not these variants were seen in the homozygous, heterozygous or compound heterozygous form. Therefore, evaluating the pathogenicity of heterozygous missense variants in ALMS1 as causative of cardiomyopathy is not possible. According to ExAC, ALMS1 is tolerant of both synonymous (z= -2.46) and missense (z= -6.40) change, while it is intolerant to loss-of-function change (pLI= 0.00). This observation agrees with available case data: published cases of Alström syndrome are caused by a loss-of-function of both copies of the ALMS1 gene. Case data (not including our patient): none ClinVar: not present Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change" Conservation data: The proline at codon 2237 is highly conserved across species. Population data: Highest MAF in European NF population: 0.002382%. The variant was reported online in 3 of 138082 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 3 of 62976 individuals of European NF descent (0.002382%.). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 27, 2022 | The p.P2237L variant (also known as c.6710C>T), located in coding exon 8 of the ALMS1 gene, results from a C to T substitution at nucleotide position 6710. The proline at codon 2237 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at