ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.6707C>T (p.Pro2236Leu) (rs201737248)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000535146 SCV000631796 uncertain significance Alstrom syndrome 2017-02-24 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2237 of the ALMS1 protein (p.Pro2237Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs201737248, ExAC 0.002%) but has not been reported in the literature in individuals with an ALMS1-related disease. 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 (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786094 SCV000924732 uncertain significance not provided 2018-01-09 no assertion criteria provided provider interpretation 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;, 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).

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